|
1
|
R S A, R M, Sastri KT, G S M, A R A, V B. Precision medicine advances in cystic fibrosis: Exploring genetic pathways for targeted therapies. Life Sci 2024; 358:123186. [PMID: 39471902 DOI: 10.1016/j.lfs.2024.123186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/14/2024] [Accepted: 10/24/2024] [Indexed: 11/01/2024]
Abstract
Personalized medicine has transformed the treatment of cystic fibrosis (CF), providing customized therapeutic approaches based on individual genetic profiles. This review explores the genetic foundations of CF, focusing on mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and their implications for the development of the disease. The advent of genetic testing has enabled the association of specific mutations to disease severity, leading to the development of CFTR modulators like Ivacaftor, Lumacaftor, and Tezacaftor. Beyond CFTR mutations, genetic modifiers, including gene replacement therapy, genetic manipulation, lentivirus, and non-viral gene therapy formulations, along with environmental factors, play critical roles in influencing disease expression and outcomes. The identification of these modifiers is essential for optimizing therapeutic strategies. Emerging biomarkers, including inflammatory markers and pulmonary function indicators, aid in early disease detection and monitoring progression. Omics technologies are uncovering novel biomarkers, enabling more precise disease management. Pharmacogenomics has become integral to CF care, allowing for personalized approaches that consider genetic variations influencing drug metabolism, especially in antibiotics and anti-inflammatory therapies. The future of CF treatment lies in precision therapies, including CFTR modulators and cutting-edge techniques like gene therapy and CRISPR-Cas9 for mutation correction. As research evolves, these advances can improve patient outcomes while minimizing adverse effects. Ethical considerations and regulatory challenges remain critical as personalized medicine advances, ensuring equitable access and the long-term effectiveness of these innovative therapies.
Collapse
Affiliation(s)
- Abinesh R S
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Mysuru, India
| | - Madhav R
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Mysuru, India
| | - K Trideva Sastri
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Mysuru, India.
| | - Meghana G S
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Mysuru, India
| | - Akhila A R
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Mysuru, India
| | - Balamuralidhara V
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Mysuru, India
| |
Collapse
|
|
2
|
Miyakawa-Tanaka K, Suzuki J, Hirasawa Y, Nakamura S, Takeda K, Narumoto O, Matsui H. Positive correlation between voriconazole trough concentrations and C-reactive protein levels in patients with chronic pulmonary aspergillosis: A retrospective cohort study. J Infect Chemother 2023; 29:683-687. [PMID: 36965708 DOI: 10.1016/j.jiac.2023.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/13/2023] [Accepted: 03/17/2023] [Indexed: 03/27/2023]
Abstract
BACKGROUND Voriconazole (VRCZ) is the first-line treatment for chronic pulmonary aspergillosis (CPA). VRCZ trough concentration monitoring is recommended for adequate therapy because VRCZ concentrations vary widely. However, factors associated with variations in VRCZ concentrations, especially in the same patient at different time points, have not been identified. The objective of this study was to identify factors influencing VRCZ trough concentrations. PATIENTS AND METHODS This single-center retrospective study conducted at our institute between April 2014 and August 2016 included patients with CPA who received VRCZ. Patient trough concentrations were measured more than twice while the patients received the same dose using the same administration route (defined as one series). A step-wise method and multiple regression analysis were used to test the effects of patient characteristics on VRCZ trough concentrations. RESULTS Sixty-nine series in 49 patients were analyzed. VRCZ was administered orally in 59 series, intravenously in 7 series, and by dry syrup in 3 series. The median VRCZ trough concentration and the median variation in VRCZ concentrations were 1.68 and 0.99 μg/ml, respectively. In the simple regression analysis, creatinine, alkaline phosphatase, C-reactive protein (CRP), and creatinine clearance significantly correlated with VRCZ concentrations. Multiple regression analysis demonstrated a significant positive correlation between CRP and VRCZ concentration (P < 0.0001). CONCLUSION In patients with CPA, VRCZ concentration correlated with CRP levels in the same patients receiving the same dose of VRCZ at different time points.
Collapse
Affiliation(s)
- Kazuko Miyakawa-Tanaka
- Center for Pulmonary Disease, National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
| | - Junko Suzuki
- Center for Pulmonary Disease, National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
| | - Yasutaka Hirasawa
- Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Sumie Nakamura
- Center for Pulmonary Disease, National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
| | - Keita Takeda
- Center for Pulmonary Disease, National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
| | - Osamu Narumoto
- Center for Pulmonary Disease, National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
| | - Hirotoshi Matsui
- Center for Pulmonary Disease, National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
| |
Collapse
|
|
3
|
Takesue Y, Hanai Y, Oda K, Hamada Y, Ueda T, Mayumi T, Matsumoto K, Fujii S, Takahashi Y, Miyazaki Y, Kimura T. Clinical Practice Guideline for the Therapeutic Drug Monitoring of Voriconazole in Non-Asian and Asian Adult Patients: Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. Clin Ther 2022; 44:1604-1623. [DOI: 10.1016/j.clinthera.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/18/2022] [Accepted: 10/28/2022] [Indexed: 11/23/2022]
|
|
4
|
Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis. Pharmacogenet Genomics 2022; 32:257-267. [PMID: 35947050 DOI: 10.1097/fpc.0000000000000470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. METHODS We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity. RESULTS A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. CONCLUSION IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.
Collapse
|
|
5
|
Voriconazole-Induced Hepatotoxicity Concise up-to-date review. JOURNAL OF BASIC AND CLINICAL HEALTH SCIENCES 2022. [DOI: 10.30621/jbachs.1051669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
|
|
6
|
Bennett MJ, Balcerek MI, Lewis EAD, Zhang RLL, Bachmeier C, Tey S, Faux S, Girgis L, Greenfield JR, Lazarus S. Voriconazole‐Associated Periostitis: New Insights into Pathophysiology and Management. JBMR Plus 2021; 6:e10557. [PMID: 35229058 PMCID: PMC8861987 DOI: 10.1002/jbm4.10557] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/07/2021] [Indexed: 11/11/2022] Open
Abstract
Voriconazole‐associated periostitis (VAP) is an underrecognized and unpredictable side effect of long‐term voriconazole therapy. We report two cases of VAP occurring in the post‐transplant setting: a 68‐year‐old lung transplant recipient who required ongoing voriconazole therapy, in whom urinary alkalinization was used to promote fluoride excretion and minimize voriconazole‐related skeletal toxicity, and a 68‐year‐old stem‐cell transplant recipient with a high voriconazole dose requirement, identified on pharmacogenomic testing to be a CYP2C19 ultrarapid metabolizer, the dominant enzyme in voriconazole metabolism. This is the first reported case of pharmacogenomic profiling in VAP and may explain the variability in individual susceptibility to this uncommon adverse effect. Our findings provide new insights into both the management and underlying pathophysiology of VAP. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Michael J Bennett
- Department of Endocrinology and Diabetes St Vincent's Hospital Darlinghurst Australia
- St Vincent's Clinical School, UNSW Medicine Darlinghurst Australia
| | - Matthew I Balcerek
- Department of Endocrinology and Diabetes Royal Brisbane and Women's Hospital Herston Australia
| | - Edward AD Lewis
- Department of Rehabilitation Sacred Heart Health Service, St Vincent's Hospital Darlinghurst Australia
| | - Roland LL Zhang
- Heart and Lung Transplant Unit St Vincent's Hospital Darlinghurst Australia
| | - Caroline Bachmeier
- Chemical Pathology Pathology Queensland, Royal Brisbane and Women's Hospital Herston Australia
| | - Siok Tey
- Department of Haematology and Bone Marrow Transplantation Royal Brisbane and Women's Hospital Herston Australia
| | - Steven Faux
- Department of Rehabilitation Sacred Heart Health Service, St Vincent's Hospital Darlinghurst Australia
| | - Laila Girgis
- Department of Rheumatology St Vincent's Hospital Darlinghurst Australia
| | - Jerry R Greenfield
- Department of Endocrinology and Diabetes St Vincent's Hospital Darlinghurst Australia
| | - Syndia Lazarus
- Department of Endocrinology and Diabetes Royal Brisbane and Women's Hospital Herston Australia
- School of Clinical Medicine – Royal Brisbane Clinical Unit The University of Queensland Herston Australia
| |
Collapse
|
|
7
|
Burke A, Smith D, Coulter C, Bell SC, Thomson R, Roberts JA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Drug Treatment of Non-Tuberculous Mycobacteria in Cystic Fibrosis. Clin Pharmacokinet 2021; 60:1081-1102. [PMID: 33982266 DOI: 10.1007/s40262-021-01010-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2021] [Indexed: 10/21/2022]
Abstract
Non-tuberculous mycobacteria (NTM) are an emerging group of pulmonary infectious pathogens of increasing importance to the management of patients with cystic fibrosis (CF). NTM include slow-growing mycobacteria such as Mycobacterium avium complex (MAC) and rapidly growing mycobacteria such as Mycobacterium abscessus. The incidence of NTM in the CF population is increasing and infection contributes to significant morbidity to the patient and costs to the health system. Treating M. abscessus requires the combination of multiple costly antibiotics for months, with potentially significant toxicity associated with treatment. Although international guidelines for the treatment of NTM infection in CF are available, there are a lack of robust pharmacokinetic studies in CF patients to inform dosing and drug choice. This paper aims to outline the pharmacokinetic and pharmacodynamic factors informing the optimal treatment of NTM infections in CF.
Collapse
Affiliation(s)
- Andrew Burke
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland School of Medicine, Brisbane, QLD, Australia
| | - Daniel Smith
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland School of Medicine, Brisbane, QLD, Australia
| | - Chris Coulter
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland School of Medicine, Brisbane, QLD, Australia
| | - Scott C Bell
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland School of Medicine, Brisbane, QLD, Australia.,QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Rachel Thomson
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland School of Medicine, Brisbane, QLD, Australia.,Immunology Department, Gallipoli Medical Research Institute, Brisbane, QLD, Australia
| | - Jason A Roberts
- Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia. .,Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. .,Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. .,Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
| |
Collapse
|
|
8
|
Zhang Y, Hou K, Liu F, Luo X, He S, Hu L, Yang C, Huang L, Feng Y. The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis. Mycoses 2021; 64:860-873. [PMID: 33896064 DOI: 10.1111/myc.13293] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/10/2021] [Accepted: 04/15/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. OBJECTIVES The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. METHODS Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. RESULTS Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2 = 44%, p < .00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2 = 46%, p < .00001) had significantly higher voriconazole Cmin (μg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2 = 0%, p = .0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2 = 22%, p = .003). Similarly, the Cmin /D (μg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2 = 0%, p = .002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2 = 0%, p = .003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2 = 0%, p < .00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2 = 50%, p = .005). CONCLUSIONS Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.
Collapse
Affiliation(s)
- Ying Zhang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Kelu Hou
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Fang Liu
- Department of Mathematics and Physics, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, China
| | - Xingxian Luo
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Shiyu He
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Lei Hu
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Changqing Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lin Huang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Yufei Feng
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| |
Collapse
|
|
9
|
Gautier-Veyret E, Thiebaut-Bertrand A, Roustit M, Bolcato L, Depeisses J, Schacherer M, Schummer G, Fonrose X, Stanke-Labesque F. Optimization of voriconazole therapy for treatment of invasive aspergillosis: Pharmacogenomics and inflammatory status need to be evaluated. Br J Clin Pharmacol 2020; 87:2534-2541. [PMID: 33217017 DOI: 10.1111/bcp.14661] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 11/04/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
AIMS Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (<1 mg/L). METHODS The genetic score was determined in hematological patients treated with VRC. The higher the genetic score, the faster the metabolism of the patient. The impact of the genetic score was evaluated considering initial VRC Cmin and all VRC Cmin (n = 159) determined during longitudinal therapeutic drug monitoring. RESULTS Forty-three patients were included, of whom 41 received VRC for curative indication. Thirty-six patients had a genetic score ≥2, of whom 11 had an initial insufficient VRC Cmin . A genetic score ≥2 had a positive predictive value of 0.31 for having an initial insufficient VRC Cmin and initial VRC Cmin was not associated with the genetic score. The lack of association between the genetic score and VRC Cmin may be related to the inflammatory status of the patients (C-reactive protein [CRP] levels: median [Q1-Q3]: 43.0 [11.0-110.0] mg/L), as multivariate analysis performed on all VRC Cmin identified CRP as an independent determinant of the VRC Cmin adjusted for dose (P < .0001). CONCLUSION The combined genetic score did not predict low VRC exposure in patients with inflammation, which is frequent in patients with invasive fungal infections. Strategies for the individualization of VRC dose should integrate the inflammatory status of patients in addition to pharmacogenetic variants.
Collapse
Affiliation(s)
- Elodie Gautier-Veyret
- Inserm, CHU Grenoble Alpes, HP2, Universitaire Grenoble Alpes, Grenoble, 38000, France
| | | | - Matthieu Roustit
- Inserm, CHU Grenoble Alpes, HP2, Universitaire Grenoble Alpes, Grenoble, 38000, France
| | - Léa Bolcato
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, CHU Grenoble Alpes, France
| | | | | | - Gabriel Schummer
- Univ. Grenoble Alpes, Inserm, CHU Grenoble Alpes, HP2, Grenoble, France
| | - Xavier Fonrose
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, CHU Grenoble Alpes, France
| | | |
Collapse
|
|
10
|
Teng GJ, Bai XR, Zhang L, Liu HJ, Nie XH. Remission of hepatotoxicity in chronic pulmonary aspergillosis patients after lowering trough concentration of voriconazole. World J Clin Cases 2020; 8:4700-4707. [PMID: 33195637 PMCID: PMC7642544 DOI: 10.12998/wjcc.v8.i20.4700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/29/2020] [Accepted: 08/31/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chronic pulmonary aspergillosis (CPA) is a rare syndrome that is often accompanied by gradual lung tissue destruction. Voriconazole is usually employed as the first-line agent for CPA treatment. However, some patients can develop hepatotoxicity and often were forced to stop voriconazole treatment.
AIM To record the improving trend of liver function and the therapeutic effects in patients after lowering the trough concentration of voriconazole.
METHODS This study retrospectively analyzed 12 adult CPA patients who developed hepatotoxicity during the voriconazole treatment. In these patients, the oral dose was reduced to 3/4 or 1/2 of the standard dose (4 mg/kg, twice daily), and the lower limit of voriconazole trough concentration was maintained more than 0.5 µg/mL. The trend of remission of liver toxicity after drug reduction in 12 patients was recorded. During the same period, 25 patients who received standard doses served as the control group. Data from the two groups were collected and analyzed for different parameters such as demographic characteristics, underlying pulmonary disorders, laboratory tests, and therapeutic effect. The differences between the two groups were statistically compared.
RESULTS Hepatotoxicity occurred in 12 patients within 28-65 d after oral voriconazole treatment. Hepatotoxicity was mainly manifested by the significantly increased level of gamma-glutamyltransferase and a slight increase of alanine aminotransferase and aspartate aminotransferase. The oral dose of voriconazole was reduced to approximately 3 mg/kg in seven patients and approximately 2 mg/kg in five patients. The average trough concentrations for the 12 patients before and after voriconazole oral dose reduction were 3.17 ± 1.47 µg/mL (1.5-6.0 µg/mL) and 1.70 ± 0.78 µg/mL (0.6-3.3 µg/mL), respectively (P = 0.02). After lowering the trough concentrations, the hepatotoxicity was alleviated in all the patients. However, gamma-glutamyltransferase levels declined slowly. After 4 mo of treatment, 7 of the 12 patients were successfully treated in the low trough concentrations group (41.7%). Similarly, 8 of the 25 patients in the standard treatment dose group (32.0%) were effectively treated. There was no statistical difference between the groups (P = 0.72).
CONCLUSION Reducing the lower limit of the voriconazole trough concentration to 0.5 µg/mL can alleviate the hepatotoxicity and maintained certain clinical efficacy in CPA patients; however, patients should be closely monitored.
Collapse
Affiliation(s)
- Guo-Jie Teng
- Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Xiang-Rong Bai
- Pharmacy Department, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Lin Zhang
- Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Hong-Jun Liu
- Department of Evidence-based Medicine, Xuanwu Hospital Capital Medical University, Beijing, China, Beijing 100053, China
| | - Xiu-Hong Nie
- Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| |
Collapse
|
|
11
|
Lee J, Ng P, Hamandi B, Husain S, Lefebvre MJ, Battistella M. Effect of Therapeutic Drug Monitoring and Cytochrome P450 2C19 Genotyping on Clinical Outcomes of Voriconazole: A Systematic Review. Ann Pharmacother 2020; 55:509-529. [DOI: 10.1177/1060028020948174] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objectives To examine current knowledge on the clinical utility of therapeutic drug monitoring (TDM) in voriconazole therapy, the impact of CYP2C19 genotype on voriconazole plasma concentrations, and the role of CYP2C19 genotyping in voriconazole therapy. Data Sources Three literature searches were conducted for original reports on (1) TDM and voriconazole outcomes and (2) voriconazole and CYP2C19 polymorphisms. Searches were conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception to June 2020. Study Selection and Data Extraction Randomized controlled trials, cohort studies, and case series with ≥10 patients were included. Only full-text references in English were eligible. Data Synthesis A total of 63 studies were reviewed. TDM was recommended because of established concentration and efficacy/toxicity relationships. Voriconazole trough concentrations ≥1.0 mg/L were associated with treatment success; supratherapeutic concentrations were associated with increased neurotoxicity; and hepatotoxicity associations were more prevalent in Asian populations. CYP2C19 polymorphisms significantly affect voriconazole metabolism, but no relationship with efficacy/safety were found. Genotype-guided dosing with TDM was reported to increase chances of achieving therapeutic range. Relevance to Patient Care and Clinical Practice Genotype-guided dosing with TDM is a potential solution to optimizing voriconazole efficacy while avoiding treatment failures and common toxicities. Conclusions Voriconazole plasma concentrations and TDM are treatment outcome predictors, but research is needed to form a consensus target therapeutic range and dosage adjustment guidelines based on plasma concentrations. CYP2C19 polymorphisms are a predictor of voriconazole concentrations and metabolism, but clinical implications are not established. Large-scale, high-methodological-quality trials are required to investigate the role for prospective genotyping and establish CYP2C19-guided voriconazole dosing recommendations.
Collapse
Affiliation(s)
| | - Patrick Ng
- University Health Network, Toronto, ON, Canada
| | - Bassem Hamandi
- University of Toronto, ON, Canada
- University Health Network, Toronto, ON, Canada
| | - Shahid Husain
- University of Toronto, ON, Canada
- University Health Network, Toronto, ON, Canada
| | | | - Marisa Battistella
- University of Toronto, ON, Canada
- University Health Network, Toronto, ON, Canada
| |
Collapse
|
|
12
|
Wilk MA, Braun AT, Farrell PM, Laxova A, Brown DM, Holt JM, Birch CL, Sosonkina N, Wilk BM, Worthey EA. Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis. Cold Spring Harb Mol Case Stud 2020; 6:a004531. [PMID: 32014855 PMCID: PMC6996517 DOI: 10.1101/mcs.a004531] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/16/2019] [Indexed: 12/18/2022] Open
Abstract
Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis.
Collapse
Affiliation(s)
- Melissa A Wilk
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
| | - Andrew T Braun
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
| | - Philip M Farrell
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
| | - Anita Laxova
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
| | - Donna M Brown
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
| | - James M Holt
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
| | - Camille L Birch
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
| | - Nadiya Sosonkina
- Department of Genetics, University of Alabama-Birmingham, Birmingham, Alabama 35233, USA
| | - Brandon M Wilk
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
| | - Elizabeth A Worthey
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
- Department of Genetics, University of Alabama-Birmingham, Birmingham, Alabama 35233, USA
| |
Collapse
|
|
13
|
Hicks JK, Quilitz RE, Komrokji RS, Kubal TE, Lancet JE, Pasikhova Y, Qin D, So W, Caceres G, Kelly K, Salchert YS, Shahbazian K, Abbas-Aghababazadeh F, Fridley BL, Velez AP, McLeod HL, Greene JN. Prospective CYP2C19-Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations. Clin Pharmacol Ther 2019; 107:563-570. [PMID: 31549389 DOI: 10.1002/cpt.1641] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 09/14/2019] [Indexed: 11/11/2022]
Abstract
A risk mitigation strategy was implemented to determine if a higher prophylactic voriconazole dosage in patients with CYP2C19 rapid metabolizer neutropenic acute myeloid leukemia (AML) reduces the incidence of subtherapeutic trough concentrations. Patients with AML (n = 263) were preemptively genotyped for CYP2C19*2, *3, and *17 alleles as part of a single-center prospective, interventional, quality improvement study. CYP2C19 rapid metabolizers (CYP2C19*1/*17) were recommended to receive interventional voriconazole 300 mg twice daily, ultrarapid metabolizers (CYP2C19*17/*17) were recommended to avoid voriconazole, and all others received the standard prophylactic dosage of 200 mg twice daily. In this real-world setting, 202 patients (76.8%) were prescribed prophylactic voriconazole, and of these patients 176 (87.1%) received CYP2C19-guided prophylactic dosing. Voriconazole trough concentrations were obtained for 41 of the 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole. Interventional voriconazole resulted in higher plasma trough concentrations (median 2.7 μg/mL) compared with the standard prophylactic dosage (median 0.6 μg/mL; P = 0.001). Subtherapeutic concentrations were avoided in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosage compared to 46.2% receiving standard dosage (P = 0.02). CYP2C19 genotyping to preemptively guide prophylactic voriconazole dosing is feasible and may be a potential strategy for reducing the risk of subtherapeutic trough concentrations that potentiate breakthrough fungal infections.
Collapse
Affiliation(s)
- J Kevin Hicks
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Rod E Quilitz
- Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Rami S Komrokji
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Timothy E Kubal
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jeffrey E Lancet
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Yanina Pasikhova
- Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Dahui Qin
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Wonhee So
- Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Gisela Caceres
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Kerry Kelly
- Department of Clinical Informatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Yasmina S Salchert
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Kevin Shahbazian
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Farnoosh Abbas-Aghababazadeh
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Ana P Velez
- Department of Infectious Disease, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Howard L McLeod
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - John N Greene
- Department of Infectious Disease, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| |
Collapse
|
|
14
|
Individualized Medication of Voriconazole: A Practice Guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. Ther Drug Monit 2019; 40:663-674. [PMID: 30192314 PMCID: PMC6250289 DOI: 10.1097/ftd.0000000000000561] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Supplemental Digital Content is Available in the Text. Background: Voriconazole (VRZ) is a second-generation triazole antifungal agent with broad-spectrum activity. It is available in both intravenous and oral formulations, and is primarily indicated for treating invasive aspergillosis. The most commonly used dose for adults is 4 mg/kg or 200 mg twice daily. VRZ presents nonlinear pharmacokinetics in adults, whereas drug–drug interactions and cytochrome P450 2C19 (CYP2C19) polymorphism are of great concern for VRZ. Because the liquid chromatography method has been widely used for measuring VRZ blood concentration, and target VRZ blood concentration has been recommended in some guidelines regarding efficacy and safety, therapeutic drug monitoring is considered as a useful tool for VRZ-individualized medication. Also, the CYP2C19 genotype test is available for guiding relevant drugs use in some health care facilities. Our objective was to develop an evidence-based practice guideline for VRZ-individualized medication. Methods: We followed the latest guideline definition from the Institute of Medicine and referred to the World Health Organization handbook for guideline development. The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2015CN001). The guideline is, in principle, targeted at all Chinese health care providers. The quality of evidence and strength of the recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. Results: Twenty-six recommendations were formulated regarding therapeutic drug monitoring, special groups of patients, drug safety, off-indication use, and drug–drug interactions. Of them, 12 were strong recommendations. Most quality of evidence was low, very low, or expert opinions. Conclusions: We developed an evidence-based practice guideline for VRZ-individualized medication, which provided comprehensive and practical recommendations for health care providers. The development of the guideline exposed several research gaps to improve VRZ use.
Collapse
|
|
15
|
Gautier-Veyret E, Truffot A, Bailly S, Fonrose X, Thiebaut-Bertrand A, Tonini J, Cahn JY, Stanke-Labesque F. Inflammation is a potential risk factor of voriconazole overdose in hematological patients. Fundam Clin Pharmacol 2018; 33:232-238. [PMID: 30306637 DOI: 10.1111/fcp.12422] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/06/2018] [Accepted: 10/05/2018] [Indexed: 12/19/2022]
Abstract
Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin ) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi-square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.
Collapse
Affiliation(s)
- Elodie Gautier-Veyret
- Univ. Grenoble Alpes, HP2, Grenoble, F-38041, France.,INSERM U1042, Grenoble, 38041, France.,Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| | - Aurélie Truffot
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| | - Sébastien Bailly
- Univ. Grenoble Alpes, HP2, Grenoble, F-38041, France.,INSERM U1042, Grenoble, 38041, France.,Grenoble Alpes University Hospital, EFCR Laboratory, Pôle THORAX and VESSELS, Grenoble, 38043, France
| | - Xavier Fonrose
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| | - Anne Thiebaut-Bertrand
- TIMC-TheREx, UMR 5525, CNRS, La Tronche, 38041, France.,Service d'Hématologie Clinique, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| | - Julia Tonini
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| | - Jean-Yves Cahn
- TIMC-TheREx, UMR 5525, CNRS, La Tronche, 38041, France.,Service d'Hématologie Clinique, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| | - Françoise Stanke-Labesque
- Univ. Grenoble Alpes, HP2, Grenoble, F-38041, France.,INSERM U1042, Grenoble, 38041, France.,Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, Centre Hospitalier Universitaire des Alpes, Grenoble, 38043, France
| |
Collapse
|
|
16
|
Mangal N, Hamadeh I, Arwood MJ, Cavallari LH, Samant TS, Klinker KP, Bulitta J, Schmidt S. Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults. Clin Pharmacol Ther 2018; 104:957-965. [PMID: 29315506 PMCID: PMC6037619 DOI: 10.1002/cpt.1012] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 01/02/2018] [Accepted: 01/03/2018] [Indexed: 11/10/2022]
Abstract
Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady-state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5-7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model-based approach to predict doses that can maximize the net benefit (probability of efficacy-probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label-recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40-50% patients, with net benefit ranging from 5.8-61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300-600 mg were found to maximize the net benefit up to 51-66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.
Collapse
Affiliation(s)
- Naveen Mangal
- Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL
| | - Issam Hamadeh
- Levine Cancer Institute, Department of Cancer Pharmacology, Charlotte, NC
| | - Meghan J. Arwood
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL
| | - Larisa H. Cavallari
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL
| | | | - Kenneth P. Klinker
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL
| | - Jurgen Bulitta
- Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL
| | - Stephan Schmidt
- Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL
| |
Collapse
|
|
17
|
Xu RA, Gu EM, Liu TH, Ou-Yang QG, Hu GX, Cai JP. The effects of cytochrome P450 2C19 polymorphism on the metabolism of voriconazole in vitro. Infect Drug Resist 2018; 11:2129-2135. [PMID: 30464555 PMCID: PMC6219421 DOI: 10.2147/idr.s179078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background CYP/CYP450 2C19 (CYP2C19) is a highly polymorphic enzyme and exhibits individual differences in metabolic activity. The purpose of this research was mainly to explore the catalytic activities of 30 CYP2C19 variants on the substrate voriconazole in vitro, including 24 novel CYP2C19 variants (2C19.2E-.2H, .2J, .3C, .29-.33, L16F, 35FS, R124Q, R125G, T130M, N231T, M255T, R261W, N277K, S303N, I327T, N403I, and A430V) found in Chinese Han population for the first time. Methods These CYP2C19 variants were expressed in Spodoptera frugiperda (Sf) 21 insect cells using the baculovirus-mediated expression system. The substrate voriconazole was incubated with the abovementioned proteins at 37°C for 30 minutes in an appropriate designed system. Then through detecting its major metabolite voriconazole N-oxide by ultra-performance liquid chromatography tandem mass spectrometry, available data were obtained to explain the influence of CYP2C19 polymorphisms on voriconazole. Results From the results, when compared to CYP2C19.1, most variants exhibited either reduced Vmax and/or increased Km value, indicating that the intrinsic clearance (Vmax/Km) values of most variants were significantly altered. The catalytic activities of 20 novel variants exhibited decreases in different degrees compared to CYP2C19.1, with relative clearance values ranging from 1.11% to 83.78%. However, L16F exhibited the increased catalytic activity for 135.68%. In addition, the kinetic parameters of four variants (2C19.2H, .3, 35FS, and R124Q) could not be detected, due to the defective gene. Conclusion This is the first study to report the effects of CYP2C19 polymorphisms on vori-conazole metabolism in vitro, and we hope these data could lay the foundation for the early clinical research and individualized treatment.
Collapse
Affiliation(s)
- Ren-Ai Xu
- Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Er-Min Gu
- Department of Pharmacy, The First People's Hospital of Jiashan, Jiaxing, Zhejiang, China
| | - Teng-Hui Liu
- Department of Pharmacology, School of Pharmaceutical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang, China,
| | - Qiu-Geng Ou-Yang
- Department of Pharmacology, School of Pharmaceutical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang, China,
| | - Guo-Xin Hu
- Department of Pharmacology, School of Pharmaceutical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang, China,
| | - Jian-Ping Cai
- Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Pharmacology, School of Pharmaceutical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang, China,
| |
Collapse
|
|
18
|
Wasko JA, Ustun C, Birkenbach M, Faizer R, Green JS. The challenges of treating aspergillus abdominal aneurysm after hematopoietic cell transplant: Rapid voriconazole metabolizer. J Oncol Pharm Pract 2017; 25:703-705. [PMID: 29285995 DOI: 10.1177/1078155217748471] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mycotic aneurysms are a fatal manifestation of disseminated fungal infections in immunocompromised hosts. We present a patient with an Aspergillus mycotic aneurysm after hematopoietic cell transplant. Due to CYP2C19 rapid metabolizer phenotype (*1/*17), therapeutic levels of voriconazole were unobtainable. Successful therapy was achieved with posaconazole salvage therapy and early, aggressive surgery. This case demonstrates the consequences of voriconazole rapid metabolism and the potential impact of genetic variants.
Collapse
Affiliation(s)
- Justin A Wasko
- 1 Department of Pharmacy, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Celalettin Ustun
- 2 Department of Medicine, Division of Hematology-Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Mark Birkenbach
- 3 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Rumi Faizer
- 4 Department of Surgery, Division of Vascular Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Jaime S Green
- 5 Department of Medicine, Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, USA
| |
Collapse
|
|
19
|
Amsden JR, Gubbins PO. Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy. Expert Opin Drug Metab Toxicol 2017; 13:1135-1146. [DOI: 10.1080/17425255.2017.1391213] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Jarrett R. Amsden
- Department of Pharmacy Practice, Butler University College of Pharmacy and Health Sciences, Indianapolis, IN, USA
| | - Paul O. Gubbins
- Division of Pharmacy Practice and Administration, UMKC School of Pharmacy at MSU, Springfield, MO, USA
| |
Collapse
|
|
20
|
Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections. Pharmacogenet Genomics 2017; 27:190-196. [PMID: 28306618 DOI: 10.1097/fpc.0000000000000277] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs. PATIENT AND METHODS Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations. RESULTS Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64-19.24, P=0.0044). CONCLUSION Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.
Collapse
|
|
21
|
Barbarino JM, Owusu-Obeng A, Klein TE, Altman RB. PharmGKB summary: voriconazole pathway, pharmacokinetics. Pharmacogenet Genomics 2017; 27:201-209. [PMID: 28277330 PMCID: PMC5405706 DOI: 10.1097/fpc.0000000000000276] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Julia M. Barbarino
- Department of Biomedical Data Science, Stanford University, California, USA
| | - Aniwaa Owusu-Obeng
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Teri E. Klein
- Department of Biomedical Data Science, Stanford University, California, USA
| | - Russ B. Altman
- Department of Genetics, Stanford University, California, USA
- Department of Bioengineering, Stanford University, California, USA
| |
Collapse
|
|
22
|
Isvoran A, Louet M, Vladoiu DL, Craciun D, Loriot MA, Villoutreix BO, Miteva MA. Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism. Drug Discov Today 2016; 22:366-376. [PMID: 27693711 DOI: 10.1016/j.drudis.2016.09.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 07/22/2016] [Accepted: 09/20/2016] [Indexed: 12/18/2022]
Abstract
Pharmacogenomics investigates DNA and RNA variations in the human genome related to drug responses. Cytochrome P450 (CYP) is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 90% of human drugs. Among the major CYP isoforms, the CYP2C subfamily is of clinical significance because it metabolizes approximately 20% of clinically administrated drugs and represents several variant alleles leading to adverse drug reactions or altering drug efficacy. Here, we review recent progress on understanding the interindividual variability of the CYP2C members and the functional and clinical impact on drug metabolism. We summarize current advances in the molecular modeling of CYP2C polymorphisms and discuss the structural bases and molecular mechanisms of amino acid variants of CYP2C members that affect drug metabolism.
Collapse
Affiliation(s)
- Adriana Isvoran
- Department of Biology and Chemistry, West University of Timisoara, 16 Pestalozzi, Timisoara 300115, Romania; Advanced Environmental Research Laboratories, West University of Timisoara, 4 Oituz, Timisoara 300086, Romania
| | - Maxime Louet
- Université Paris Diderot, Sorbonne Paris Cité, Inserm UMR-S 973, Molécules Thérapeutiques In silico, 39 rue Helene Brion, 75013 Paris, France; INSERM, U973, Paris, France
| | - Diana Larisa Vladoiu
- Department of Biology and Chemistry, West University of Timisoara, 16 Pestalozzi, Timisoara 300115, Romania; Advanced Environmental Research Laboratories, West University of Timisoara, 4 Oituz, Timisoara 300086, Romania
| | - Dana Craciun
- Teacher Training Department, West University of Timisoara, Blvd. V. Parvan, Timisoara 300223, Romania
| | - Marie-Anne Loriot
- INSERM UMR_S1147, Centre Universitaire des Saints-Pères, 45 rue des saints-Pères, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Service de Biochimie, 20 rue Leblanc, 75015 Paris, France
| | - Bruno O Villoutreix
- Université Paris Diderot, Sorbonne Paris Cité, Inserm UMR-S 973, Molécules Thérapeutiques In silico, 39 rue Helene Brion, 75013 Paris, France; INSERM, U973, Paris, France
| | - Maria A Miteva
- Université Paris Diderot, Sorbonne Paris Cité, Inserm UMR-S 973, Molécules Thérapeutiques In silico, 39 rue Helene Brion, 75013 Paris, France; INSERM, U973, Paris, France.
| |
Collapse
|
|
23
|
Effect of cytochrome P450 2C19 polymorphisms on the clinical outcomes of voriconazole: a systematic review and meta-analysis. Eur J Clin Pharmacol 2016; 72:1185-1193. [PMID: 27388292 DOI: 10.1007/s00228-016-2089-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 06/27/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19, could influence voriconazole pharmacokinetics. The association between CYP2C19 polymorphisms and voriconazole clinical outcomes is not well established. The aim of this meta-analysis was to evaluate the effect of CYP2C19 polymorphisms on clinical outcomes in patients treated with voriconazole. METHODS PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases were searched from their inception to January 2016 to identify eligible trials that reported voriconazole exposure and clinical outcomes of voriconazole according to CYP2C19 polymorphisms. Two reviewers independently reviewed the citations, extracted the data, and assessed the quality of the trials. The meta-analysis was performed using RevMan5.3. RESULTS A total of ten studies involving 598 patients were included. Compared with patients with extensive metabolizer (EM) phenotype, patients with poor metabolizer (PM) phenotype had significantly higher trough concentrations (MD, 1.22 mg/L; 95 % confidence interval (CI), 0.72-1.71; P < 0.0001). PM phenotype was also associated with a higher treatment success rate compared with EM phenotype (risk ratio (RR), 1.31; 95 % CI, 1.04-1.67; P = 0.02). However, there was no significant association between CYP2C19 polymorphisms and daily maintenance dose, overall adverse events, hepatotoxicity, and neurotoxicity. CONCLUSIONS Patients with CYP2C19 PM phenotype were associated with increased treatment success rate and trough concentrations as compared with those with EM phenotype. There was no significant association between CYP2C19 polymorphisms and either daily maintenance dose or adverse outcomes of voriconazole. However, large-scale, high-quality trials are still needed to confirm these findings.
Collapse
|
|
24
|
Hicks JK, Gonzalez BE, Zembillas AS, Kusick K, Murthy S, Raja S, Gordon SM, Hanna R. Invasive Aspergillus infection requiring lobectomy in a CYP2C19 rapid metabolizer with subtherapeutic voriconazole concentrations. Pharmacogenomics 2016; 17:663-7. [PMID: 27143031 DOI: 10.2217/pgs-2015-0014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Individuals who carry the CYP2C19*17 gain-of-function allele have lower voriconazole exposure and are therefore at risk of failing therapy. Utilizing CYP2C19 genotype to optimize voriconazole dosage may be a cost-effective method of improving treatment outcomes. However, there are limited data describing what initial voriconazole dosage should be used in those with increased CYP2C19 metabolic capacity. Herein, we present a case report of a pediatric CYP2C19 rapid metabolizer (i.e., CYP2C19*1/*17) requiring a voriconazole dosage of 14 mg/kg twice daily (usual pediatric dosage ranges from 7 to 9 mg/kg twice daily). This case report supports the clinical utility of using CYP2C19 genotype to guide voriconazole dosing, and provides data for establishing an initial voriconazole dose in pediatric CYP2C19 rapid metabolizers.
Collapse
Affiliation(s)
- J Kevin Hicks
- Pharmacy Department, Cleveland Clinic, Cleveland, OH, USA.,Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Blanca E Gonzalez
- Medicine Institute, Infectious Disease Department, Cleveland Clinic, Cleveland, OH, USA
| | | | - Karissa Kusick
- Pharmacy Department, Cleveland Clinic, Cleveland, OH, USA
| | - Sudish Murthy
- Heart & Vascular Institute, Thoracic & Cardiovascular Surgery Department, Cleveland Clinic, Cleveland, OH, USA
| | - Siva Raja
- Heart & Vascular Institute, Thoracic & Cardiovascular Surgery Department, Cleveland Clinic, Cleveland, OH, USA
| | - Steven M Gordon
- Medicine Institute, Infectious Disease Department, Cleveland Clinic, Cleveland, OH, USA
| | - Rabi Hanna
- Children's Hospital & Pediatrics Institute, Hematology & Oncology Department, Cleveland Clinic, Cleveland, OH, USA
| |
Collapse
|
|
25
|
Chuwongwattana S, Jantararoungtong T, Chitasombat MN, Puangpetch A, Prommas S, Dilokpattanamongkol P, Watcharananan SP, Sukasem C. A prospective observational study of CYP2C19 polymorphisms and voriconazole plasma level in adult Thai patients with invasive aspergillosis. Drug Metab Pharmacokinet 2016; 31:117-22. [PMID: 26861072 DOI: 10.1016/j.dmpk.2015.12.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 12/10/2015] [Accepted: 12/27/2015] [Indexed: 01/22/2023]
Abstract
The aim of this study was to investigate the association of genetic variants of CYP2C19 (CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles) and voriconazole trough plasma concentrations in Thai patients with invasive fungal infection. A total of 285 samples from patients with invasive fungal infection and treated with voriconazole were prospectively enrolled. At steady state, trough voriconazole concentrations were measured using tandem mass spectrophotometry and high performance liquid chromatography. The genetic variants in the CYP2C19 gene were genotyped for CYP2C19*2 (G681A), CYP2C19*3 (G636A) and CYP2C19*17 (C-806T) on plasma voriconazole level. Voriconazole Ctrough levels were positively associated with CYP2C19*3. The median Ctrough level for patients with the 636GA genotype (2.109, IQR 1.054-4.166 μg/ml) was statistically significantly higher than those with the 636GG genotype (1.596, IQR 0.755-2.980 μg/ml), P = 0.046. The patients with a poor metabolizer (PM; CYP2C19*2/*2, *2/*3) had voriconazole Ctrough level of 1.900 (IQR, 1.130-3.673 μg/ml). This was statistically significantly higher than that seen with the extensive metabolizer phenotype (1.470; IQR, 0.632-2.720 μg/ml), P = 0.039. An association between CYP2C19 variant alleles and high voriconazole plasma level was identified. Therefore, determining the CYP2C19 genotype before initiation of voriconazole treatment may be useful in optimizing the dosing regimen in Thai patients with invasive fungal infections.
Collapse
Affiliation(s)
- Sumonrat Chuwongwattana
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Thawinee Jantararoungtong
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Maria N Chitasombat
- Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Apichaya Puangpetch
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Santirat Prommas
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | | | - Siriorn P Watcharananan
- Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
| |
Collapse
|
|
26
|
Addy C, Downey DG, Elborn JS. Improvements in symptomatic treatment strategies for cystic fibrosis: delivering CF care in the 21st century. Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2016.1107473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
27
|
Uckun Z, Baskak B, Ozel-Kizil ET, Ozdemir H, Devrimci Ozguven H, Suzen HS. The impact of CYP2C19 polymorphisms on citalopram metabolism in patients with major depressive disorder. J Clin Pharm Ther 2015; 40:672-9. [PMID: 26343256 DOI: 10.1111/jcpt.12320] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/28/2015] [Indexed: 11/27/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Genetic variations in drug-metabolizing enzyme genes change drug pharmacokinetics and response. CYP2C19 is a clinically important enzyme that metabolizes citalopram (CIT). The objective of this study was to determine CYP2C19 genetic polymorphisms and to evaluate the impact of these polymorphisms on the metabolism of citalopram in a sample of the Turkish population. We also assessed *17 polymorphism in healthy subjects in this population. METHODS The CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method (209 healthy individuals and 50 patients for CIT metabolism), and the plasma concentrations of CIT and demethylcitalopram (DCIT) were quantified by high-performance liquid chromatography. RESULTS AND DISCUSSION The CYP2C19*1 and *17 allele frequencies for the patient group and the healthy group were 71·0%, 18·0% and 81·1%, 18·9%, respectively. There was no significant difference between the two groups (P > 0·05). The mean plasma concentrations and the mean dose-corrected (C/D) plasma levels of DCIT were significantly higher in patients with the CYP2C19*1/*1 genotype compared to patients with CYP2C19*1/*2 and CYP2C19*2/*2 genotypes (P < 0·05). Furthermore, the mean metabolic ratio (MR, CIT/DCIT) was also significantly higher in the CYP2C19*1/*2 + CYP2C19*2/*2 genotypes (P < 0·05). On the other hand, plasma CIT, DCIT concentrations and M/R value in the CYP2C19*1/*1 genotypes were no different to those of the CYP2C19*1/*17 genotypes (P > 0·05). WHAT IS NEW AND CONCLUSION Our data suggest that CYP2C19*17 polymorphism does not have a significant effect on CIT metabolism. In contrast CYP2C19*2 polymorphism has a prominent role and is likely to contribute to interindividual variability in CIT metabolism in vivo at therapeutic doses.
Collapse
Affiliation(s)
- Z Uckun
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - B Baskak
- Psychiatry Department, School of Medicine, Ankara University, Ankara, Turkey
| | - E T Ozel-Kizil
- Psychiatry Department, School of Medicine, Ankara University, Ankara, Turkey
| | - H Ozdemir
- Department of Psychiatry, Faculty of Medicine, Kirikkale University, Kirikkale, Turkey
| | - H Devrimci Ozguven
- Psychiatry Department, School of Medicine, Ankara University, Ankara, Turkey
| | - H S Suzen
- Department of Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| |
Collapse
|
|
28
|
Chau MM, Kong DCM, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, Wilkes J, Cooper CM, Roberts JA, Marriott DJE, Worth LJ. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J 2015; 44:1364-88. [PMID: 25482746 DOI: 10.1111/imj.12600] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.
Collapse
Affiliation(s)
- M M Chau
- Pharmacy Department, The Royal Melbourne Hospital, Melbourne Health, Parkville, Victoria
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Bennis Y, Bodeau S, Bouquié R, Deslandes G, Verstuyft C, Gruson B, Andréjak M, Lemaire-Hurtel AS, Chouaki T. High metabolic N-oxidation of voriconazole in a patient with refractory aspergillosis and CYP2C19*17/*17 genotype. Br J Clin Pharmacol 2015; 80:782-4. [PMID: 26138512 DOI: 10.1111/bcp.12713] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 06/01/2015] [Accepted: 06/29/2015] [Indexed: 11/30/2022] Open
Affiliation(s)
- Youssef Bennis
- Laboratory of pharmacology and toxicology, CHU Amiens Picardie, UPJV, INSERM U1088, France
| | - Sandra Bodeau
- Laboratory of pharmacology and toxicology, CHU Amiens Picardie, UPJV, INSERM U1088, France
| | - Régis Bouquié
- Laboratory of pharmacology and toxicology, Nantes University Hospital, France
| | - Guillaume Deslandes
- Laboratory of pharmacology and toxicology, Nantes University Hospital, France
| | - Céline Verstuyft
- Department of Pharmacology, EA 4123, Le Kremlin Bicêtre University Hospital, Universite Paris Sud, France
| | | | - Michel Andréjak
- Laboratory of pharmacology and toxicology, CHU Amiens Picardie, France
| | | | | |
Collapse
|
|
30
|
Weigel JD, Hunfeld NGM, Koch BCP, Egal M, Bakker J, van Schaik RHN, van Gelder T. Gain-of-function single nucleotide variants of the CYP2C19 gene (CYP2C19*17) can identify subtherapeutic voriconazole concentrations in critically ill patients: a case series. Intensive Care Med 2015; 41:2013-4. [PMID: 26239729 DOI: 10.1007/s00134-015-4002-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2015] [Indexed: 10/23/2022]
Affiliation(s)
- Joachim D Weigel
- Department of Intensive Care Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
| | - Nicole G M Hunfeld
- Department of Intensive Care Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.,Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Birgit C P Koch
- Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Mohamud Egal
- Department of Intensive Care Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - Jan Bakker
- Department of Intensive Care Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands.,Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
|
31
|
Chawla PK, Nanday SR, Dherai AJ, Soman R, Lokhande RV, Naik PR, Ashavaid TF. Correlation of CYP2C19 genotype with plasma voriconazole levels: a preliminary retrospective study in Indians. Int J Clin Pharm 2015; 37:925-30. [PMID: 26024717 DOI: 10.1007/s11096-015-0143-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 05/20/2015] [Indexed: 11/24/2022]
Abstract
BACKGROUND Voriconazole is an antifungal drug essentially metabolized by cytochrome P450 (CYP2C19) isozyme. Plasma voriconazole levels exhibit wide inter-individual variability due to several factors like age, weight, food or drug interactions or CYP2C19 polymorphisms. OBJECTIVE In the present study, we assessed the correlation of voriconazole levels with CYP2C19 genotype in patients on voriconazole therapy. SETTING Biochemistry Department of a 480 inpatient bed tertiary care hospital in India. METHODS Plasma voriconazole estimation was done in seventy-two patients on standard weight based voriconazole therapy by High Performance Liquid Chromatography (HPLC) while genotype assessment for the CYP2C19*2 and *3 was done by PCR-RFLP and *17 by ARMS-PCR. Statistical analysis and genotype-phenotype correlation was done by comparing the drug levels with the CYP2C19 genotype. MAIN OUTCOME MEASURE CYP2C19 polymorphisms influence voriconazole metabolism. RESULTS A wide variability is seen in plasma levels with only 51% attaining therapeutic levels. The allele frequency of *2, *3 and *17 variant were found to be 33.3, 0.7 and 18% respectively. The drug levels in carriers of *2 allele (poor metabolizers) was twofold higher than that in extensive metabolizers. However, the influence of *2 allele was compromised in presence of *17 allele and patients had low voriconazole levels. In addition to the genotype, co-medication and clinical condition remarkably influenced voriconazole concentration. CONCLUSION Plasma voriconazole levels are influenced by CYP2C19 variants, drug interactions and clinical condition of the patient. Genotype assessment at initiation of therapy followed by drug monitoring would help optimizing therapeutic efficacy and minimizing toxicity.
Collapse
Affiliation(s)
- Prerna K Chawla
- Research Laboratories, P.D. Hinduja Hospital and Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India
| | - Shweta R Nanday
- Department of Laboratory Medicine, P.D. Hinduja Hospital & Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India
| | - Alpa J Dherai
- Research Laboratories, P.D. Hinduja Hospital and Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India.,Department of Laboratory Medicine, P.D. Hinduja Hospital & Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India
| | - Rajeev Soman
- Department of Internal Medicine, P.D. Hinduja Hospital & Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India
| | - Rohan V Lokhande
- Department of Laboratory Medicine, P.D. Hinduja Hospital & Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India
| | - Prasad R Naik
- Department of Laboratory Medicine, P.D. Hinduja Hospital & Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India
| | - Tester F Ashavaid
- Research Laboratories, P.D. Hinduja Hospital and Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India. .,Department of Laboratory Medicine, P.D. Hinduja Hospital & Medical Research Centre, V.S. Marg, Mahim, Mumbai, 400016, India.
| |
Collapse
|
|
32
|
Moriyama B, Kadri S, Henning SA, Danner RL, Walsh TJ, Penzak SR. Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole. CURRENT FUNGAL INFECTION REPORTS 2015; 9:74-87. [PMID: 26918067 DOI: 10.1007/s12281-015-0219-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Voriconazole is an antifungal triazole that is the first line agent for treatment of invasive aspergillosis. It is metabolized by CYP2C19, CYP2C9, and CYP3A4 and demonstrates wide interpatient variability in serum concentrations. Polymorphisms in CYP2C19 contribute to variability in voriconazole pharmacokinetics. Here, evidence is examined for the use of voriconazole therapeutic drug monitoring (TDM) and the role of CYP2C19 genotyping in voriconazole dosing. The majority of studies exploring the impact of voriconazole TDM on efficacy and safety have found TDM to be beneficial. However, most of these studies are observational, with only one being a randomized controlled trial. High-volume multicenter randomized controlled trials of TDM are currently not available to support definitive guidelines. There is a significant relationship in healthy volunteers between CYP2C19 genotype and voriconazole pharmacokinetics, but this association is markedly less visible in actual patients. While CYP2C19 genotype data may explain variability of voriconazole serum levels, they alone are not sufficient to guide initial dosing. The timeliness of availability of CYP2C19 genotype data in treatment of individual patients also remains challenging. Additional studies are needed before implementation of CYP2C19 genotyping for voriconazole dosing into routine clinical care.
Collapse
Affiliation(s)
- Brad Moriyama
- NIH Clinical Center, Pharmacy Department, Bethesda, MD
| | - Sameer Kadri
- NIH Clinical Center, Critical Care Medicine Department, Bethesda, MD
| | | | - Robert L Danner
- NIH Clinical Center, Critical Care Medicine Department, Bethesda, MD
| | - Thomas J Walsh
- Transplantation-Oncology Infectious Diseases Program, Department of Medicine, Pediatrics, and Microbiology and Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY
| | - Scott R Penzak
- Department of Pharmacotherapy University of North Texas System College of Pharmacy, Fort Worth, TX
| |
Collapse
|
|
33
|
Hicks JK, Crews KR, Flynn P, Haidar CE, Daniels CC, Yang W, Panetta JC, Pei D, Scott JR, Molinelli AR, Broeckel U, Bhojwani D, Evans WE, Relling MV. Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes. Pharmacogenomics 2015; 15:1065-78. [PMID: 25084200 DOI: 10.2217/pgs.14.53] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
AIM Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele. MATERIALS & METHODS A linear mixed effect model compared voriconazole dose-corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharmacokinetics was described by a two-compartment model with Michaelis-Menten elimination. RESULTS Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 homozygotes never attained therapeutic concentrations, and had lower dose-corrected voriconazole concentrations (median 0.01 μg/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median 0.07 μg/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*17/*17 diplotype. CONCLUSION Younger age and the presence of CYP2C19 gain-of-function alleles were associated with subtherapeutic voriconazole concentrations. Starting doses based on age and CYP2C19 status could increase the number of patients achieving therapeutic voriconazole exposure.
Collapse
Affiliation(s)
- J Kevin Hicks
- Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels. Antimicrob Agents Chemother 2015; 59:2305-14. [PMID: 25645831 DOI: 10.1128/aac.04838-14] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Voriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRC Cmin throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC Cmin (n = 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC Cmin inter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC Cmin (r = 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC Cmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRC Cmin/D than patients with a genetic score of >2 (P = 0.009). Subsequent VRC Cmin remained influenced by the genetic score (P = 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC Cmin in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC Cmin within the therapeutic range.
Collapse
|
|
35
|
Trubiano JA, Crowe A, Worth LJ, Thursky KA, Slavin MA. Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort. J Antimicrob Chemother 2015; 70:1161-5. [PMID: 25558073 DOI: 10.1093/jac/dku529] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD. METHODS As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured. RESULTS The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%). CONCLUSIONS Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.
Collapse
Affiliation(s)
- J A Trubiano
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
| | - A Crowe
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
| | - L J Worth
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
| | - K A Thursky
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - M A Slavin
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia
| |
Collapse
|
|
36
|
Wang T, Zhu H, Sun J, Cheng X, Xie J, Dong H, Chen L, Wang X, Xing J, Dong Y. Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections. Int J Antimicrob Agents 2014; 44:436-42. [DOI: 10.1016/j.ijantimicag.2014.07.013] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/22/2014] [Accepted: 07/03/2014] [Indexed: 11/28/2022]
|
|
37
|
Wong JY, Kuzel P, Mullen J, Lien D, Mahmood M, Conrad C, Fiorillo L. Cutaneous squamous cell carcinoma in two pediatric lung transplant patients on prolonged voriconazole treatment. Pediatr Transplant 2014; 18:E200-7. [PMID: 25039541 DOI: 10.1111/petr.12320] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/12/2014] [Indexed: 01/06/2023]
Abstract
Oral voriconazole is commonly used for treatment and prophylaxis of invasive fungal disease post-LTx. Development of cutaneous SCC has been described in adult LTx recipients, although it is extremely rare in children. We describe two Caucasian children who developed cutaneous SCC beyond three yr post-LTx. Both developed severe photosensitivity, actinic keratosis and required curative surgical excision of the cutaneous SCC lesions. Neither patient developed metastatic lesions nor had allograft dysfunction as a result of the SCC or the change in medical treatments. The effect of voriconazole on the development of malignant skin lesions is discussed and a recommendation on dermatologic surveillance, preventive measures against phototoxicity and early treatment of SCC are provided.
Collapse
Affiliation(s)
- Jackson Y Wong
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Obeng AO, Egelund EF, Alsultan A, Peloquin CA, Johnson JA. CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy 2014; 34:703-18. [PMID: 24510446 PMCID: PMC4082739 DOI: 10.1002/phar.1400] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Since its approval by the U.S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, aspergillosis and candidiasis. Despite voriconazole's widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole's pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.
Collapse
Affiliation(s)
- Aniwaa Owusu Obeng
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Pharmacy, The Mount Sinai Hospital, New York, New York, USA
| | - Eric F. Egelund
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA
| | - Abdullah Alsultan
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA
| | - Charles A. Peloquin
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA
| | - Julie A. Johnson
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| |
Collapse
|
|
39
|
Abstract
Personalised medicine refers to a tailored approach to treatment of an individual based on molecular analysis of genes, proteins or metabolites, and commonly involves a companion diagnostic test. It usually applies to small subsets of patients, often with rare diseases. In cystic fibrosis (CF), the best example is the CFTR (CF transmembrane conductance regulator) potentiator, ivacaftor, relevant to the 5% of cystic fibrosis patients with the p.Gly551Asp gene mutation. However the cost of personalised medicine is too high, making it unaffordable in the long term for many healthcare systems. Society needs to find a way to make personalised medicine affordable in order to not deny life-changing treatments from patients.
Collapse
Affiliation(s)
- Ian M Balfour-Lynn
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London.
| |
Collapse
|
|
40
|
Wang T, Chen S, Sun J, Cai J, Cheng X, Dong H, Wang X, Xing J, Dong W, Yao H, Dong Y. Identification of factors influencing the pharmacokinetics of voriconazole and the optimization of dosage regimens based on Monte Carlo simulation in patients with invasive fungal infections. J Antimicrob Chemother 2014; 69:463-470. [DOI: 10.1093/jac/dkt369] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023] Open
|
|
41
|
Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev 2014; 26:505-25. [PMID: 23824371 DOI: 10.1128/cmr.00005-13] [Citation(s) in RCA: 184] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.
Collapse
|
|
42
|
Kim SH, Lee DG, Kwon JC, Lee HJ, Cho SY, Park C, Kwon EY, Park SH, Choi SM, Choi JH, Yoo JH. Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population. Infect Chemother 2013; 45:406-14. [PMID: 24475354 PMCID: PMC3902809 DOI: 10.3947/ic.2013.45.4.406] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 09/18/2013] [Accepted: 10/16/2013] [Indexed: 01/28/2023] Open
Abstract
Background Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established. Materials and Methods In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L. Results A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively). Conclusions While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.
Collapse
Affiliation(s)
- Si-Hyun Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - Dong-Gun Lee
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Catholic Blood and Marrow Transplantation Center, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Jae-Cheol Kwon
- Department of Internal Medicine, Daniel Medical Center, Bucheon, Korea
| | - Hyo-Jin Lee
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Sung-Yeon Cho
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Chulmin Park
- Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Eun-Young Kwon
- Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Sun Hee Park
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Su-Mi Choi
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Jung-Hyun Choi
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Jin-Hong Yoo
- Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Vaccine Bio Research Institute, The Catholic University of Korea College of Medicine, Seoul, Korea
| |
Collapse
|
|
43
|
Williams K, Mansh M, Chin-Hong P, Singer J, Arron ST. Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients. Clin Infect Dis 2013; 58:997-1002. [PMID: 24363331 DOI: 10.1093/cid/cit940] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
This article synthesizes the current data regarding the implication of voriconazole in the development of skin cancer in organ transplant recipients (OTRs) and offers suggestions for additional research. According to Organ Procurement and Transplantation Network data, 28 051 solid organ transplants were performed in 2012. Due to advancements in immunosuppression and management of infectious diseases, survival of OTRs has substantially increased. Voriconazole is a widely prescribed antifungal medication used for prophylaxis and for treatment of invasive fungal infections in OTRs. Case reports describing skin cancer associated with voriconazole exposure emerged shortly after US Food and Drug Administration approval of the drug, and it is now established that voriconazole is an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. The mechanism of voriconazole-induced skin cancer is still unknown and may involve its primary metabolite, voriconazole N-oxide. Here we discuss the current data and potential mechanisms of voriconazole-associated photosensitivity and carcinogenesis and identify areas that require further research.
Collapse
|
|
44
|
Lee SJ. Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine. Front Genet 2013; 3:318. [PMID: 23378847 PMCID: PMC3561709 DOI: 10.3389/fgene.2012.00318] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 12/20/2012] [Indexed: 12/12/2022] Open
Abstract
More than 30 years of genetic research on the CYP2C19 gene alone has identified approximately 2,000 reference single nucleotide polymorphisms (rsSNPs) containing 28 registered alleles in the P450 Allele Nomenclature Committee and the number continues to increase. However, knowledge of CYP2C19 SNPs remains limited with respect to biological functions. Functional information on the variant is essential for justifying its clinical use. Only common variants (minor allele frequency >5%) that represent CYP2C19*2, *3, *17, and others have been mostly studied. Discovery of new genetic variants is outstripping the generation of knowledge on the biological meanings of existing variants. Alternative strategies may be needed to fill this gap. The present study summarizes up-to-date knowledge on functional CYP2C19 variants discovered in phenotyped humans studied at the molecular level in vitro. Understanding the functional meanings of CYP2C19 variants is an essential step toward shifting the current medical paradigm to highly personalized therapeutic regimens.
Collapse
Affiliation(s)
- Su-Jun Lee
- Department of Pharmacology, Pharmacogenomics Research Center, Inje University College of Medicine, Inje University Busan, South Korea
| |
Collapse
|
|
45
|
Markantonis SL, Katelari A, Pappa E, Doudounakis S. Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis. J Cyst Fibros 2012; 11:246-52. [DOI: 10.1016/j.jcf.2011.12.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 12/21/2011] [Accepted: 12/29/2011] [Indexed: 10/14/2022]
|
|
46
|
Current World Literature. Curr Opin Pulm Med 2011; 17:484-8. [DOI: 10.1097/mcp.0b013e32834c7beb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
47
|
Cytotoxicity of voriconazole on cultured human corneal endothelial cells. Antimicrob Agents Chemother 2011; 55:4519-23. [PMID: 21768517 DOI: 10.1128/aac.00569-11] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The purpose of the present study was to evaluate the toxicity of voriconazole on cultured human corneal endothelial cells (HCECs). HCECs were cultured and exposed to various concentrations of voriconazole (5.0 to 1,000 μg/ml). Cell viability was measured using a Cell Counting Kit-8 (CCK-8) and live/dead viability/cytotoxicity assays. Cell damage was assessed using phase-contrast microscopy after 24 h of exposure to voriconazole. To analyze the effect of voriconazole on the intercellular barrier, immunolocalization of zonula occludens 1 (ZO1) was performed. A flow cytometric assay was performed to evaluate the apoptotic and necrotic effects of voriconazole on HCECs. Cytotoxicity tests demonstrated the dose-dependent toxic effect of voriconazole on HCECs. Voriconazole concentrations of ≥100 μg/ml led to a significant reduction in cell viability. The morphological characteristics of HCECs also changed in a dose-dependent manner. Increasing concentrations of voriconazole resulted in fading staining for ZO1. Higher concentrations of voriconazole resulted in an increased number of propidium iodide (PI)-positive cells, indicating activation of the proapoptotic pathway. In conclusion, voriconazole may have a dose-dependent toxic effect on cultured HCECs. The results of this study suggest that although voriconazole concentrations of up to 50 μg/ml do not decrease cell viability, intracameral voriconazole concentrations of ≥100 μg/ml may increase the risk of corneal endothelial damage.
Collapse
|
|
48
|
Mikus G, Scholz IM, Weiss J. Pharmacogenomics of the triazole antifungal agent voriconazole. Pharmacogenomics 2011; 12:861-72. [DOI: 10.2217/pgs.11.18] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Genetic polymorphisms in drug-metabolizing enzymes are frequently responsible for high variability in the pharmacokinetics of certain drugs leading to large variations in drug efficacy and adverse drug effects, or large ranges of the doses required for optimal drug efficacy. Voriconazole is a triazole antifungal agent which has been available for several years and has potent in vitro and in vivo activity against a broad spectrum of medically important pathogens, including Aspergillus, Cryptococcus and Candida. Voriconazole is extensively metabolized by the cytochrome P450 system with CYP2C19 being the major route for elimination. Thus, polymorphisms in the CYP2C19 gene have substantial impact on the pharmacokinetics of voriconazole and its interactions with other drugs. This article summarizes the current knowledge regarding CYP2C19 and discusses the influences of other drug-metabolizing enzymes and drug transporters on voriconazole disposition.
Collapse
Affiliation(s)
| | - Ina Maria Scholz
- Department of Dermatology, University Hospital of Heidelberg, Voßstraße 2, 69115 Heidelberg, Germany
| | - Johanna Weiss
- Department of Clinical Pharmacology & Pharmacoepidemiology, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| |
Collapse
|