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Sato T, Kawabata T, Kumondai M, Hayashi N, Komatsu H, Kikuchi Y, Onoguchi G, Sato Y, Nanatani K, Hiratsuka M, Maekawa M, Yamaguchi H, Abe T, Tomita H, Mano N. Effect of Organic Anion Transporting Polypeptide 1B1 on Plasma Concentration Dynamics of Clozapine in Patients with Treatment-Resistant Schizophrenia. Int J Mol Sci 2024; 25:13228. [PMID: 39684938 DOI: 10.3390/ijms252313228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
The involvement of drug-metabolizing enzymes and transporters in plasma clozapine (CLZ) dynamics has not been well examined in Japanese patients with treatment-resistant schizophrenia (TRS). Therefore, this clinical study investigated the relationship between single nucleotide polymorphisms (SNPs) of various pharmacokinetic factors (drug-metabolizing enzymes and transporters) and dynamic changes in CLZ. Additionally, we aimed to determine whether CLZ acts as a substrate for pharmacokinetic factors using in vitro assays and molecular docking calculations. We found that 6 out of 10 patients with TRS and with multiple organic anion transporting polypeptide (OATP) variants (OATP1B1: *1b, *15; OATP1B3: 334T>G, 699G>A; and OATP2B1: *3, 935G>A, 601G>A, 76_84del) seemed to be highly exposed to CLZ and/or N-desmethyl CLZ. A CLZ uptake study using OATP-expressing HEK293 cells showed that CLZ was a substrate of OATP1B1 with Km and Vmax values of 38.9 µM and 2752 pmol/mg protein/10 min, respectively. The results of molecular docking calculations supported the differences in CLZ uptake among OATP molecules and the weak inhibitory effect of cyclosporine A, which is a strong inhibitor of OATPs, on CLZ uptake via OATP1B1. This is the first study to show that CLZ is an OATP1B1 substrate and that the presence of SNPs in OATPs potentially alters CLZ pharmacokinetic parameters.
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Affiliation(s)
- Toshihiro Sato
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Takeshi Kawabata
- Graduate School of Information Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Masaki Kumondai
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Nagomi Hayashi
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Hiroshi Komatsu
- Department of Psychiatry, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Yuki Kikuchi
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Go Onoguchi
- Department of Psychiatry, Tohoku University Hospital, Sendai 980-8574, Japan
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Yu Sato
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Kei Nanatani
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan
| | - Masahiro Hiratsuka
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan
| | - Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
| | - Hiroaki Yamaguchi
- Department of Pharmacy, Yamagata University Hospital, Yamagata 990-9585, Japan
- Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
| | - Takaaki Abe
- Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8574, Japan
- Division of Medical Science, Graduate School of Biomedical Engineering, Tohoku University, Sendai 980-8579, Japan
- Department of Clinical Biology and Hormonal Regulation, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Hiroaki Tomita
- Department of Psychiatry, Tohoku University Hospital, Sendai 980-8574, Japan
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Nariyasu Mano
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
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Qi L, Ma B, Fan H, Qi S, Yang F, An H. Case report: Time response of plasma clozapine concentrations on cessation of heavy smoking. Front Pharmacol 2024; 15:1408915. [PMID: 38974031 PMCID: PMC11224526 DOI: 10.3389/fphar.2024.1408915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/05/2024] [Indexed: 07/09/2024] Open
Abstract
Smoking cessation in patients treated with clozapine might lead to elevated plasma concentrations and severe side effects. This case report investigated the trajectory of clozapine plasma concentrations over time after smoking cessation in a Chinese inpatient with schizophrenia. This case report delineates the temporal response of plasma clozapine concentrations and dose-corrected clozapine plasma concentrations in a 33-year-old inpatient with schizophrenia who had a substantial smoking history and ceased smoking abruptly during dose titration. This case report presents a sudden increase in plasma clozapine concentrations and dose-corrected plasma clozapine concentrations after smoking cessation, followed by a rapid decline in dose-corrected plasma clozapine concentrations during the initial 2 weeks and a return to pre-cessation levels approximately 1 month later. The findings suggest that clinicians and pharmacists should adjust clozapine dosage in accordance with changes in smoking status, taking into consideration the temporal effects. Post-smoking cessation adjustments to clozapine dosage should be coupled with therapeutic drug monitoring, especially for patients with heavy smoking habits. Moreover, the advice of the clinical pharmacist should be considered in complex cases to ensure safe use of clozapine.
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Affiliation(s)
| | | | | | | | - Fude Yang
- Peking University, HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Huimei An
- Peking University, HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
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Berneri M, Jha U, O'Halloran S, Salman S, Wickramasinghe S, Kendrick K, Nguyen J, Joyce DA. Validation of Population Pharmacokinetic Models for Clozapine Dosage Prediction. Ther Drug Monit 2024; 46:217-226. [PMID: 38446630 DOI: 10.1097/ftd.0000000000001184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/03/2023] [Indexed: 03/08/2024]
Abstract
BACKGROUND Clozapine is unique in its capacity to ameliorate severe schizophrenia but at high risk of toxicity. A relationship between blood concentration and clinical response and evidence for concentration-response relationships to some adverse effects justify therapeutic drug monitoring of clozapine. However, the relationship between drug dose and blood concentration is quite variable. This variability is, in part, due to inductive and inhibitory interactions varying the activity of cytochrome P450 1A2 (CYP1A2), the principal pathway for clozapine elimination. Several population pharmacokinetic models have been presented to facilitate dose selection and to identify poor adherence in individual patients. These models have faced little testing for validity in independent populations or even for persisting validity in the source population. METHODS Therefore, we collected a large population of clozapine-treated patients (127 patients, 1048 timed plasma concentrations) in whom dosing and covariate information could be obtained with high certainty. A population pharmacokinetic model was constructed with data collected in the first 6 weeks from study enrolment (448 plasma concentrations), to estimate covariate influences and to allow alignment with previously published models. The model was tested for its performance in predicting the concentrations observed at later time intervals up to 5 years. The predictive performances of 6 published clozapine population models were then assessed in the entire population. RESULTS The population pharmacokinetic model based on the first 6 weeks identified significant influences of sex, smoking, and cotreatment with fluvoxamine on clozapine clearance. The model built from the first 6 weeks had acceptable predictive performance in the same patient population up to the first 26 weeks using individual parameters, with a median predictive error (PE) of -0.1% to -15.9% and median absolute PE of 22.9%-27.1%. Predictive performance fell progressively with time after 26 weeks. Bayesian addition of plasma concentration observations within each prediction period improved individual predictions. Three additional observations extended acceptable predictive performance into the second 6 months of therapy. When the published models were tested with the entire data set, median PE ranged from -8% to +35% with a median absolute PE of >39% in all models. Thus, none of the tested models was successful in external validation. Bayesian addition of single patient observations improved individual predictions from all models but still without achieving acceptable performances. CONCLUSIONS We conclude that the relationship between covariates and blood clozapine concentrations differs between populations and that relationships are not stable over time within a population. Current population models for clozapine are not capturing influential covariates.
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Affiliation(s)
- Massimo Berneri
- Schools of Medicine & Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia
| | - Uma Jha
- Schools of Medicine & Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia
| | - Seán O'Halloran
- Clinical Pharmacology & Toxicology, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia
| | - Sam Salman
- Clinical Pharmacology & Toxicology, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia
- Medical School, University of Western Australia, Crawley, Western Australia, Australia
| | | | - Kevin Kendrick
- Fremantle Hospital Mental Health Service, Fremantle, Western Australia, Australia
| | - Jessica Nguyen
- Department of Pharmacy, Graylands Hospital, Mount Claremont, Western Australia, Australia ; and
| | - David A Joyce
- Schools of Medicine & Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia
- Clinical Pharmacology & Toxicology, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia
- Department of Clinical Pharmacology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
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Kingston E, Tingle M, Bellissima BL, Helsby N, Burns K. CYP-catalysed cycling of clozapine and clozapine- N-oxide promotes the generation of reactive oxygen species in vitro. Xenobiotica 2024; 54:26-37. [PMID: 38108307 DOI: 10.1080/00498254.2023.2294473] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 12/10/2023] [Indexed: 12/19/2023]
Abstract
Clozapine is an effective atypical antipsychotic indicated for treatment-resistant schizophrenia, but is under-prescribed due to the risk of severe adverse drug reactions such as myocarditis.A mechanistic understanding of clozapine cardiotoxicity remains elusive.This study aimed to investigate the contribution of selected CYP isoforms to cycling between clozapine and its major circulating metabolites, N-desmethylclozapine and clozapine-N-oxide, with the potential for reactive species production.CYP supersome™-based in vitro techniques were utilised to quantify specific enzyme activity associated with clozapine, clozapine-N-oxide and N-desmethylclozapine metabolism.The formation of reactive species within each incubation were quantified, and known intermediates detected.CYP3A4 predominately catalysed clozapine-N-oxide formation from clozapine and was associated with concentration-dependent reactive species production, whereas isoforms favouring the N-desmethylclozapine pathway (CYP2C19 and CYP1A2) did not produce reactive species.Extrahepatic isoforms CYP2J2 and CYP1B1 were also associated with the formation of clozapine-N-oxide and N-desmethylclozapine but did not favour one metabolic pathway over another.Unique to this investigation is that various CYP isoforms catalyse clozapine-N-oxide reduction to clozapine.This process was associated with the concentration-dependent formation of reactive species with CYP3A4, CYP1B1 and CYP1A1 that did not correlate with known reactive intermediates, implicating metabolite cycling and reactive oxygen species in the mechanism of clozapine-induced toxicity.
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Affiliation(s)
- Ellen Kingston
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
| | - Malcolm Tingle
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
| | - Brandi L Bellissima
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
| | - Nuala Helsby
- Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand
| | - Kathryn Burns
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
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Yéléhé-Okouma M, Charrois-Sciaudeau S, Tyvaert L, Bertoni N, Gambier N. Therapeutic drug monitoring as an essential tool to ensure clozapine efficacy and prevent its toxicity in smokers: a case report. Eur J Clin Pharmacol 2023; 79:1713-1715. [PMID: 37740750 DOI: 10.1007/s00228-023-03574-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/18/2023] [Indexed: 09/25/2023]
Affiliation(s)
- Mélissa Yéléhé-Okouma
- Department of Clinical Pharmacology, Clinical Toxicology, Pharmacovigilance and Addictovigilance (CEIP-A), Regional University Hospital of Nancy, Vandoeuvre-les-Nancy, France.
| | - Sophie Charrois-Sciaudeau
- Department of Clinical Pharmacology, Clinical Toxicology, Pharmacovigilance and Addictovigilance (CEIP-A), Regional University Hospital of Nancy, Vandoeuvre-les-Nancy, France
| | - Louise Tyvaert
- Department of Neurology, Regional University Hospital of Nancy, Vandoeuvre-les-Nancy, France
| | - Nadine Bertoni
- Unity of Clinical Psychiatry, Regional Institute of Physical Rehabilitation, Nancy, France
| | - Nicolas Gambier
- Department of Clinical Pharmacology, Clinical Toxicology, Pharmacovigilance and Addictovigilance (CEIP-A), Regional University Hospital of Nancy, Vandoeuvre-les-Nancy, France
- University of Lorraine-CNRS, IMoPA, Vandoeuvre-les-Nancy, France
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Flanagan RJ, Hunter S, Obee SJ. Effect of Cigarette Smoking on Clozapine Dose and on Plasma Clozapine and N-Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice. J Clin Psychopharmacol 2023; 43:514-519. [PMID: 37930204 DOI: 10.1097/jcp.0000000000001762] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2023]
Abstract
BACKGROUND Cigarette smoking enhances plasma clozapine clearance and thus affects the clozapine dose requirement. METHODS We compared clozapine daily dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in samples submitted for clozapine therapeutic drug monitoring (1996-2017). RESULTS There were 105,316/60,792 and 34,290/31,309 samples with dose information from male and female smokers/nonsmokers, respectively. There was information on the number of cigarettes smoked daily for 12,842 samples (8409 patients) and 3948 samples (2753 patients) from men and women, respectively. Of these, 574 and 253 samples were from men and women, respectively, who reported smoking 1-9 cigarettes daily.In both sexes, the median clozapine doses in the nonsmokers were 75%-80% of those in the smokers, but the median plasma clozapine and norclozapine concentrations were 136% higher. The effect of smoking on the dose and on median plasma clozapine and norclozapine concentrations seemed maximal after 2-3, perhaps fewer, cigarettes daily in males. In females, the effect of smoking seemed to be near maximal after some 4-5 cigarettes per day. IMPLICATIONS The optimum target range for predose plasma clozapine may be different in smokers (0.35-0.45 mg L-1) as opposed to nonsmokers (0.50-0.60 mg L-1). That changes in clozapine clearance are likely near maximal with cigarette smoking as low as 2-3 d-1 in males, perhaps slightly more in females, emphasizes that covert or passive smoking may be an important factor in seemingly random changes in plasma clozapine concentration at constant dose.
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Affiliation(s)
- Robert James Flanagan
- From the Precision Medicine, Networked Services, Bessemer Wing, King's College Hospital NHS Foundation Trust, London, United Kingdom
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Ma B, Fan H, Qi S, Yang F, An H. Effects of smoking cessation on plasma clozapine concentrations in male patients with schizophrenia during the COVID-19 pandemic. Front Psychiatry 2023; 14:1256264. [PMID: 37779619 PMCID: PMC10541223 DOI: 10.3389/fpsyt.2023.1256264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/30/2023] [Indexed: 10/03/2023] Open
Abstract
Introduction This study aimed to investigate the effect of smoking cessation on plasma clozapine (CLO) concentrations in long-term hospitalized Chinese male patients with schizophrenia treated with CLO during the COVID-19 pandemic. Methods Therapeutic drug monitoring (TDM) data for CLO were collected at Beijing HuiLongGuan Hospital between December 1, 2019 (before smoking cessation) and January 31, 2020 (after smoking cessation) in this retrospective study. Fifty-three male smokers and inpatients with schizophrenia who were treated with CLO were included. Plasma concentrations of CLO were measured using high-performance liquid chromatography-tandem mass spectrometry. The fagerstrom test for nicotine dependence (FTND) was used to assess smoking behavior. Results The plasma CLO concentrations and dose-corrected plasma CLO concentrations were significantly increased by 29.3 and 23.5%, respectively, after smoking cessation. Discussion The results suggested that clinicians and pharmacists should adjust the CLO dose based on changes in smoking status in patients stabilized with CLO during the COVID-19 pandemic. Careful TDM for CLO should be performed prior to dose adjustment，to reduce the increased risk of smoking cessation induced side effects, especially for older patients receiving multiple medications.
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Affiliation(s)
| | | | | | | | - Huimei An
- Psychiatry Research Center, HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Peking University, Beijing, China
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Tralongo F, Konecki C, Feliu C, Kaladjian A, Djerada Z. Association Between Clozapine Plasma Concentrations and Treatment Response: A Systematic Review, Meta-analysis and Individual Participant Data Meta-analysis. Clin Pharmacokinet 2023; 62:807-818. [PMID: 37145296 DOI: 10.1007/s40262-023-01247-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2023] [Indexed: 05/06/2023]
Abstract
BACKGROUND AND OBJECTIVES Although therapeutic drug monitoring of clozapine is recommended, its optimisation is often adjusted only on the basis of dosage. The aim of this study was to assess the link between clozapine plasma concentrations and clinical response by a meta-analysis of published studies and by an individual participant data meta-analysis. METHODS We conducted a computerised search of bibliographic databases (EMBASE, PubMed, Clinical Trials, and Web of Science) to identify studies that assessed the relationship between clozapine serum or plasma concentrations and clinical efficacy. Using pooled data, we investigated the association between improvement of clinical outcome and clozapine or norclozapine plasma concentrations, the sum of clozapine and norclozapine plasma concentrations, and the coefficient of variation of clozapine plasma concentrations. Using available individual data, we assessed the relationship between clozapine plasma concentrations and clinical response (changes in the Brief Psychiatric Rating Scale score) and identified a threshold level for a favourable clinical response. RESULTS Fifteen studies satisfied inclusion criteria. Our meta-analysis showed that responders had clozapine plasma concentrations that were, on average, 117 ng/mL higher than non-responders. The patients with plasma clozapine concentrations above the thresholds identified in each study had a higher likelihood of responding (odds ratio = 2.94, p < 0.001). Norclozapine plasma concentrations were not associated with a clinical response. The meta-analysis of individual data supported this result and confirmed the link between clozapine concentrations and a change in the Brief Psychiatric Rating Scale score and/or the probability of clinical response. Finally, with the analysis of the coefficient of variation of clozapine plasma concentrations, we found that a greater inter-individual fluctuation in plasma concentrations was associated with a loss of clinical response. CONCLUSIONS Our work confirmed that, in contrast to clozapine doses, clozapine plasma concentrations were related to a favourable clinical response, with a mean difference between responders and non-responders of 117 ng/mL. A threshold for a treatment response of 407 ng/mL was determined, with a high discriminatory capacity, and a sensitivity and specificity of 71% and 89.1%, respectively.
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Affiliation(s)
- Federica Tralongo
- Department of Pharmacology, University of Reims Champagne-Ardenne, HERVI EA 3801, Reims University Hospital, Reims, France
- Department of Psychiatry, Marne Public Mental Health Institution, Reims University Hospital, Reims, France
| | - Céline Konecki
- Department of Pharmacology, University of Reims Champagne-Ardenne, HERVI EA 3801, Reims University Hospital, Reims, France
| | - Catherine Feliu
- Department of Pharmacology, University of Reims Champagne-Ardenne, HERVI EA 3801, Reims University Hospital, Reims, France
| | - Arthur Kaladjian
- Department of Psychiatry, Marne Public Mental Health Institution, Reims University Hospital, Reims, France
| | - Zoubir Djerada
- Department of Pharmacology, University of Reims Champagne-Ardenne, HERVI EA 3801, Reims University Hospital, Reims, France.
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Qubad M, Bittner RA. Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia. Ther Adv Psychopharmacol 2023; 13:20451253231158152. [PMID: 36994117 PMCID: PMC10041648 DOI: 10.1177/20451253231158152] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/24/2023] [Indexed: 03/31/2023] Open
Abstract
Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.
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Affiliation(s)
- Mishal Qubad
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Robert A. Bittner
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Goethe University, Heinrich-Hoffmann-Str. 10, D-60528 Frankfurt am Main, Germany
- Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Frankfurt am Main, Germany
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Torrico TJ. The pathophysiology of rapid fluctuations in mental status associated with olanzapine: A case report. Front Psychiatry 2022; 13:1028350. [PMID: 37082516 PMCID: PMC10111197 DOI: 10.3389/fpsyt.2022.1028350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/02/2022] [Indexed: 12/02/2022] Open
Abstract
BackgroundOlanzapine toxicity is reported to be a rare but specific phenomenon characterized by rapid fluctuations between somnolence and agitation, which has been referred to as “agitation despite sedation.” A similar phenomenon is observed as an adverse reaction of the long-acting injectable olanzapine formulation, which has been referred to as “delirium/sedation syndrome.”Case presentationThis case report describes a 48-year-old man diagnosed with schizophrenia who experienced rapid fluctuations between somnolence and agitation during a cross-titration of olanzapine to clozapine. The patient had normal serum levels of both medications and the symptoms resolved with the discontinuation of olanzapine.ConclusionRapid fluctuations in mental status between somnolence and agitation are not clearly described among other antipsychotics, and it is possible that this phenomenon may be specific to olanzapine. The findings of this case report suggested that this phenomenon was likely the result of the oversaturation of (H1) and (M1) receptors.
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Affiliation(s)
- Tyler J. Torrico
- Department of Psychiatry, Kern Medical, Bakersfield, CA, United States
- American Psychiatric Association Substance Abuse and Mental Health Services Administration (SAMHSA) Minority Fellowship, Washington, DC, United States
- *Correspondence: Tyler J. Torrico,
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Leukocytosis Associated with Clozapine Treatment: A Case Series and Systematic Review of the Literature. ACTA ACUST UNITED AC 2021; 57:medicina57080816. [PMID: 34441022 PMCID: PMC8399375 DOI: 10.3390/medicina57080816] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia. Despite its superior efficacy profile as compared with other antipsychotics, clozapine remains underutilized. Clozapine monitoring systems clearly describe the proposed management of clozapine-induced neutropenia; however, no specific mention is made of how to interpret neutrophilic leukocytosis, despite that being a relatively frequent finding. Prescribers unfamiliar with this molecule may misjudge its clinical significance, potentially leading to untimely treatment interruption. Here, we systematically review the literature on the risk of neutrophilic leukocytosis during clozapine treatment, and describe eight additional cases among our patient cohort. MATERIALS AND METHODS We performed a systematic review of the literature on PubMed and Embase using the PRISMA 2020 guidelines, and selected all original reports describing either (1) the prevalence of neutrophilic leukocytosis during clozapine treatment, or (2) the clinical significance of neutrophilic leukocytosis. We described eight additional cases of neutrophilic leukocytosis during clozapine treatment while attending an outpatient psychiatric clinic. RESULTS Our research ultimately yielded the selection of 13 articles included in this systematic review. The case series highlighted the presence of stable and clinically unremarkable neutrophilia during a follow-up ranging from one to ten years. CONCLUSIONS Existing evidence indicates that leukocytosis associated with clozapine treatment can be considered as an asymptomatic and benign condition, suggesting that no change in clozapine treatment is needed upon its detection.
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Smoking and Neuropsychiatric Disease-Associations and Underlying Mechanisms. Int J Mol Sci 2021; 22:ijms22147272. [PMID: 34298890 PMCID: PMC8304236 DOI: 10.3390/ijms22147272] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/28/2021] [Accepted: 07/03/2021] [Indexed: 01/02/2023] Open
Abstract
Despite extensive efforts to combat cigarette smoking/tobacco use, it still remains a leading cause of global morbidity and mortality, killing more than eight million people each year. While tobacco smoking is a major risk factor for non-communicable diseases related to the four main groups—cardiovascular disease, cancer, chronic lung disease, and diabetes—its impact on neuropsychiatric risk is rather elusive. The aim of this review article is to emphasize the importance of smoking as a potential risk factor for neuropsychiatric disease and to identify central pathophysiological mechanisms that may contribute to this relationship. There is strong evidence from epidemiological and experimental studies indicating that smoking may increase the risk of various neuropsychiatric diseases, such as dementia/cognitive decline, schizophrenia/psychosis, depression, anxiety disorder, and suicidal behavior induced by structural and functional alterations of the central nervous system, mainly centered on inflammatory and oxidative stress pathways. From a public health perspective, preventive measures and policies designed to counteract the global epidemic of smoking should necessarily include warnings and actions that address the risk of neuropsychiatric disease.
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Whiskey E, Romano G, Elliott M, Campbell M, Anandarajah C, Taylor D, Valsraj K. Possible pharmacogenetic factors in clozapine treatment failure: a case report. Ther Adv Psychopharmacol 2021; 11:20451253211030844. [PMID: 35211290 PMCID: PMC8862186 DOI: 10.1177/20451253211030844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/18/2021] [Indexed: 01/19/2023] Open
Abstract
There is still much to learn about the predictors of therapeutic response in psychiatry, but progress is gradually being made and precision psychiatry is an exciting and emerging subspeciality in this field. This is critically important in the treatment of refractory psychotic disorders, where clozapine is the only evidence-based treatment but only about half the patients experience an adequate response. In this case report, we explore the possible biological mechanisms underlying treatment failure and discuss possible ways of improving clinical outcomes. Further work is required to fully understand why some patients fail to respond to the most effective treatment in refractory schizophrenia. Therapeutic drug monitoring together with early pharmacogenetic testing may offer a path for some patients with refractory psychotic symptoms unresponsive to clozapine treatment.
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Affiliation(s)
- Eromona Whiskey
- Pharmacy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, London, SE5 8AZ, UK
| | | | | | | | | | - David Taylor
- Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK
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van der Plas A, Pouly S, Blanc N, Haziza C, de La Bourdonnaye G, Titz B, Hoeng J, Ivanov NV, Taranu B, Heremans A. Impact of switching to a heat-not-burn tobacco product on CYP1A2 activity. Toxicol Rep 2020; 7:1480-1486. [PMID: 33204648 PMCID: PMC7649435 DOI: 10.1016/j.toxrep.2020.10.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/18/2020] [Accepted: 10/23/2020] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Cigarette smoking induces cytochrome P450 1A2 (CYP1A2) expression and activity, while smoking cessation normalizes the levels of this enzyme. The aim of this publication is to summarize the data on CYP1A2 gene expression and activity in preclinical and clinical studies on the Tobacco Heating System (THS), currently marketed as IQOS® with HEETs®, and to summarize the potential effects on CYP1A2 to be expected upon switching to reduced-risk products (RRPs). METHODS We summarized PMI's preclinical and clinical data on the effects of switching from cigarette smoking to THS. RESULTS Data from four preclinical mouse and rat studies showed that, upon either cessation of cigarette smoke exposure or switching to THS exposure, the upregulation of CYP1A2 observed with exposure to cigarette smoke reverted close to fresh-air levels. Data from four clinical studies yielded similar results on CYP1A2 activity within a time frame of five days. Furthermore, the effects of switching to THS were similar to those seen after smoking cessation. CONCLUSIONS Because smoking cessation and switching to either electronic cigarettes or THS seem to have similar effects on CYP1A2 activity, the same measures taken for patients treated with narrow therapeutic index drugs that are metabolized by CYP1A2 and who quit smoking should be recommended for those switching to RRPs.
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Affiliation(s)
- Angela van der Plas
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Sandrine Pouly
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Nicolas Blanc
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Christelle Haziza
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | | | - Bjorn Titz
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Julia Hoeng
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Nikolai V. Ivanov
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Brindusa Taranu
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
| | - Annie Heremans
- PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
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Lemaitre F, Solas C, Grégoire M, Lagarce L, Elens L, Polard E, Saint-Salvi B, Sommet A, Tod M, Barin-Le Guellec C. Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments. Fundam Clin Pharmacol 2020; 34:530-547. [PMID: 32603486 PMCID: PMC7361515 DOI: 10.1111/fcp.12586] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/17/2020] [Accepted: 06/25/2020] [Indexed: 12/25/2022]
Abstract
Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.
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Affiliation(s)
- Florian Lemaitre
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, F-35000, France.,INSERM, Centre d'Investigation Clinique, CIC 1414, Rennes, F-35000, France
| | - Caroline Solas
- Aix-Marseille University, APHM, UMR "Emergence des Pathologies Virales" Inserm 1207 IRD 190, Laboratoire de Pharmacocinétique et Toxicologie, Hôpital La Timone, Marseille, 13005, France
| | - Matthieu Grégoire
- Clinical Pharmacology Department, CHU Nantes, Nantes Cedex 1, Nantes, 44093, France.,UMR INSERM 1235, The Enteric Nervous System in Gut and Brain Disorders, University of Nantes, Nantes Cedex 1, Nantes, 44093, France
| | - Laurence Lagarce
- Service de Pharmacologie-Toxicologie et Pharmacovigilance, Centre Hospitalo-Universitaire d'Angers, Angers, 49100, France
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Louvain, Belgique.,Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCL), Louvain, Belgique
| | - Elisabeth Polard
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, F-35000, France.,INSERM, Centre d'Investigation Clinique, CIC 1414, Rennes, F-35000, France
| | - Béatrice Saint-Salvi
- Medical Interactions Unit, Agence National de Sécurité du Médicaments et des produits de santé, Saint-Denis, 93200, France
| | - Agnès Sommet
- Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, INSERM UMR 1027, CIC 1426, Toulouse University Hospital, Faculty of Medicine, University of Toulouse, Toulouse, 31000, France
| | - Michel Tod
- Pharmacy, Croix-Rousse Hospital, Lyon, 69005, France.,ISPB, University Lyon 1, Lyon, 69005, France
| | - Chantal Barin-Le Guellec
- Laboratoire de Biochimie et de Biologie Moléculaire, CHU de Tours, Tours, F37044, France.,Université de Tours, Tours, F-37044, France.,INSERM, IPPRITT, U1248, Limoges, F-87000, France
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Albitar O, Harun SN, Zainal H, Ibrahim B, Sheikh Ghadzi SM. Population Pharmacokinetics of Clozapine: A Systematic Review. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9872936. [PMID: 31998804 PMCID: PMC6970501 DOI: 10.1155/2020/9872936] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 12/10/2019] [Accepted: 12/19/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVE Clozapine is a second-generation antipsychotic drug that is considered the most effective treatment for refractory schizophrenia. Several clozapine population pharmacokinetic models have been introduced in the last decades. Thus, a systematic review was performed (i) to compare published pharmacokinetics models and (ii) to summarize and explore identified covariates influencing the clozapine pharmacokinetics models. METHODS A search of publications for population pharmacokinetic analyses of clozapine either in healthy volunteers or patients from inception to April 2019 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded. RESULTS Twelve studies were included in this review. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. Significant interindividual variations of clozapine pharmacokinetic parameters were found in most of the included studies. Age, sex, smoking status, and cytochrome P450 1A2 were found to be the most common identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models. CONCLUSIONS Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.
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Affiliation(s)
- Orwa Albitar
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, George Town, Penang, Malaysia
| | - Sabariah Noor Harun
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, George Town, Penang, Malaysia
| | - Hadzliana Zainal
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, George Town, Penang, Malaysia
| | - Baharudin Ibrahim
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, George Town, Penang, Malaysia
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Keshavarzi F, Fox T, Whiskey E, Taylor D. Change in plasma concentration of clozapine and norclozapine following a switch of oral formulation. Ther Adv Psychopharmacol 2020; 10:2045125319899263. [PMID: 31976069 PMCID: PMC6958650 DOI: 10.1177/2045125319899263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 12/09/2019] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Clozapine formulation has been shown to affect plasma concentrations of clozapine and norclozapine. Changes in formulation might result in toxicity or treatment failure. METHODS We identified, from electronic records, patients who switched from clozapine tablets to oral liquid or vice versa and compared plasma concentrations before and after the switch. RESULTS We identified 13 patients with 85 blood samples who changed formulation of clozapine. Overall mean standardized clozapine plasma level was 0.67 mg/l daily dose on liquid and 0.87 mg/l daily dose on tablets (p = 0.035). CONCLUSION Use of clozapine liquid results in lower plasma clozapine concentration than the same dose of tablets.
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Affiliation(s)
- Farinaz Keshavarzi
- Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Foundation Trust, London, UK
| | - Tony Fox
- Institute of Pharmaceutical Science, King's College London, London, UK
| | - Eromona Whiskey
- Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Foundation Trust, London, UK
| | - David Taylor
- Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Foundation Trust, Denmark Hill, London, SE5 8AZ, UK
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Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine. Clin Pharmacokinet 2019; 57:729-737. [PMID: 28866861 DOI: 10.1007/s40262-017-0591-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVE: An increasing trend in prescribing proton pump inhibitors (PPIs) inevitably increases the risk of unwanted drug-drug interactions (DDIs). The aim of this study was to uncover pharmacokinetic interactions between two PPIs-omeprazole and pantoprazole-and venlafaxine. METHODS A therapeutic drug monitoring database contained plasma concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine. We considered three groups: a group of patients who received venlafaxine without confounding medications (non-PPI group, n = 906); a group of patients who were comedicated with omeprazole (n = 40); and a group of patients comedicated with pantoprazole (n = 40). Plasma concentrations of venlafaxine, O-desmethylvenlafaxine and active moiety (venlafaxine + O-desmethylvenlafaxine), as well as dose-adjusted plasma concentrations, were compared using non-parametrical tests. RESULTS Daily doses of venlafaxine did not differ between groups (p = 0.949). The Mann-Whitney U test showed significantly higher plasma concentrations of active moiety, as well as venlafaxine and O-desmethylvenlafaxine, in both PPI groups [p = 0.023, p = 0.011, p = 0.026, +29% active moiety, +27% venlafaxine, +36% O-desmethylvenlafaxine (pantoprazole); p = 0.003, p = 0.039 and p < 0.001, +36% active moiety, +27% venlafaxine, +55% O-desmethylvenlafaxine (omeprazole)]. Significantly higher concentration-by-dose (C/D) values for venlafaxine and active moiety were detected in the pantoprazole group (p = 0.013, p = 0.006, respectively), while in the omeprazole group, C/D ratios for all three parameters-venlafaxine, O-desmethylvenlafaxine and active moiety-were significantly higher (p = 0.021, p < 0.001 and p < 0.001, respectively). CONCLUSIONS Significantly higher plasma concentrations for all parameters (venlafaxine, O-desmethylvenlafaxine, active moiety) suggest clinically relevant inhibitory effects of both PPIs, most likely on the cytochrome P450 (CYP) 2C19-mediated metabolism of venlafaxine. The findings might be the result of different degrees of CYP2C19 involvement, therefore the inhibition of CYP2C19 by both PPIs may lead to an increased metabolism via CYP2D6 to O-desmethylvenlafaxine.
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19
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20
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Maideen NMP. Tobacco smoking and its drug interactions with comedications involving CYP and UGT enzymes and nicotine. World J Pharmacol 2019; 8:14-25. [DOI: 10.5497/wjp.v8.i2.14] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/20/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Tobacco smoking is a global public health threat causing several illnesses including cardiovascular disease (Myocardial infarction), cerebrovascular disease (Stroke), peripheral vascular disease (Claudication), chronic obstructive pulmonary disease, asthma, reduced female infertility, sexual dysfunction in men, different types of cancer and many other diseases. It has been estimated in 2015 that approximately 1.3 billion people smoke, around the globe. Use of medications among smokers is more common, nowadays. This review is aimed to identify the medications affected by smoking, involving Cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferases (UGTs) enzymes and Nicotine. Polycyclic aromatic hydrocarbons (PAHs) of tobacco smoke have been associated with the induction of CYP enzymes such as CYP1A1, CYP1A2 and possibly CYP2E1 and UGT enzymes. The drugs metabolized by CYP1A1, CYP1A2, CYP2E1 and UGT enzymes might be affected by tobacco smoking and the smokers taking medications metabolized by those enzymes, may need higher doses due to decreased plasma concentrations through enhanced induction by PAHs of tobacco smoke. The prescribers and the pharmacists are required to be aware of medications affected by tobacco smoking to prevent the toxicity-associated complications during smoking cessation.
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21
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Reeve E, Moriarty F, Nahas R, Turner JP, Kouladjian O'Donnell L, Hilmer SN. A narrative review of the safety concerns of deprescribing in older adults and strategies to mitigate potential harms. Expert Opin Drug Saf 2017; 17:39-49. [PMID: 29072544 DOI: 10.1080/14740338.2018.1397625] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION As with prescribing or continuing medications, deprescribing brings with it the potential for harm as well as benefit. Uncertainty and avoidance of harm has been reported as a barrier to deprescribing in practice and may contribute to continuation of inappropriate medications. AREAS COVERED This narrative review covers four main safety concerns/potential harms of deprescribing in older adults: adverse drug withdrawal events, return of medical condition(s), reversal of drug-drug interactions and damage to the doctor-patient relationship. These are discussed in relation to medications in general, with some examples of medication classes used to illustrate the potential safety concerns. The majority of these harms can be minimized or even prevented by using a patient-centered, structured deprescribing process with planning, tapering and close monitoring during, and after medication withdrawal. EXPERT OPINION More research is needed into the safety concerns of deprescribing, however, avenues exist during drug development and post-marketing surveillance to gain knowledge on this topic. Questions remain about when it is suitable to discontinue certain medications/medication classes and there is uncertainty about the harms and benefits of both medication continuation and discontinuation in complex older adults.
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Affiliation(s)
- Emily Reeve
- a Cognitive Decline Partnership Centre, Ageing and Pharmacology, Kolling Institute of Medical Research, School of Medicine , University of Sydney , St Leonards , NSW , Australia.,b Geriatric Medicine Research , Dalhousie University Faculty of Medicine , Halifax , NS , Canada.,c Faculty of Health Professions - College of Pharmacy , Dalhousie University , Halifax , NS , Canada
| | - Frank Moriarty
- d HRB Centre for Primary Care Research, Department of General Practice , Royal College of Surgeons in Ireland , Dublin , Ireland
| | - Rayan Nahas
- e Departments of Aged Care and Clinical Pharmacology , Royal North Shore Hospital , Saint Leonards , NSW , Australia
| | - Justin P Turner
- f Centre de recherché , Universite de Montreal Institut universitaire de geriatrie de Montreal , Montreal , QC , Canada.,g Faculte de pharmacie , Universite de Montreal , Montreal , QC , Canada
| | - Lisa Kouladjian O'Donnell
- a Cognitive Decline Partnership Centre, Ageing and Pharmacology, Kolling Institute of Medical Research, School of Medicine , University of Sydney , St Leonards , NSW , Australia.,e Departments of Aged Care and Clinical Pharmacology , Royal North Shore Hospital , Saint Leonards , NSW , Australia
| | - Sarah N Hilmer
- a Cognitive Decline Partnership Centre, Ageing and Pharmacology, Kolling Institute of Medical Research, School of Medicine , University of Sydney , St Leonards , NSW , Australia.,e Departments of Aged Care and Clinical Pharmacology , Royal North Shore Hospital , Saint Leonards , NSW , Australia
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Cigarette smoking has a differential effect on the plasma level of clozapine in Taiwanese schizophrenic patients associated with the CYP1A2 gene -163A/C single nucleotide polymorphism. Psychiatr Genet 2017; 26:172-7. [PMID: 27203225 DOI: 10.1097/ypg.0000000000000139] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE The efficacy of clozapine clearance has been shown to be associated with smoking and genetic polymorphism of CYP1A2. This study aims to investigate the effect of smoking on the plasma level of clozapine in Taiwanese schizophrenic patients and its relevance to the CYP1A2 gene -163A/C single nucleotide polymorphism. MATERIALS AND METHODS A total of 143 hospitalized schizophrenic patients who had received clozapine therapy for at least 14 days were enrolled in this study. The trough plasma concentration of clozapine was measured with LC/MS/MS. The -163A/C variant in the CYP1A2 gene was identified by DNA sequencing and restriction fragment length polymorphism analysis. The effect of smoking on the clozapine level was examined by multiple linear regression analysis and its relation to the -163A/C variant of the CYP1A2 gene was analyzed using a general linear model with Bonferroni correction. RESULTS Patients with smoking habits showed a significantly lower plasma level of clozapine than those without smoking habits (P=0.022) and the difference in clozapine levels between smokers and nonsmokers appeared to be significant in the individuals carrying the homozygous -163A allele (P=0.02). It was also found that nonsmokers carrying the -163A allele tended to have higher plasma levels of clozapine. This tendency was not found in the individuals with smoking habits. CONCLUSION Cigarette smoking has a significant impact on the plasma level of clozapine in Taiwanese schizophrenic patients carrying the homozygous -163A allele in the CYP1A2 gene. Cigarette smoking may increase the clearance of clozapine in these patients.
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Potential Mechanisms of Hematological Adverse Drug Reactions in Patients Receiving Clozapine in Combination With Proton Pump Inhibitors. J Psychiatr Pract 2017; 23:114-120. [PMID: 28291036 DOI: 10.1097/pra.0000000000000223] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.
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Anderson GD, Chan LN. Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. Clin Pharmacokinet 2016; 55:1353-1368. [PMID: 27106177 DOI: 10.1007/s40262-016-0400-9] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tobacco smoke contains a large number of compounds in the form of metals, volatile gases and insoluble particles, as well as nicotine, a highly addictive alkaloid. Marijuana is the most widely used illicit drug of abuse in the world, with a significant increase in the USA due to the increasing number of states that allow medical and recreational use. Of the over 70 phytocannabinoids in marijuana, Δ9-tetrahydrocannabinol (Δ9THC), cannabidiol (CBD) and cannibinol are the three main constituents. Both marijuana and tobacco smoking induce cytochrome P450 (CYP) 1A2 through activation of the aromatic hydrocarbon receptor, and the induction effect between the two products is additive. Smoking cessation is associated with rapid downregulation of CYP1A enzymes. On the basis of the estimated half-life of CYP1A2, dose reduction of CYP1A drugs may be necessary as early as the first few days after smoking cessation to prevent toxicity, especially for drugs with a narrow therapeutic index. Nicotine is a substrate of CYP2A6, which is induced by oestrogen, resulting in lower concentrations of nicotine in females than in males, especially in females taking oral contraceptives. The significant effects of CYP3A4 inducers and inhibitors on the pharmacokinetics of Δ9THC/CBD oromucosal spray suggest that CYP3A4 is the primary enzyme responsible for the metabolism of Δ9THC and CBD. Limited data also suggest that CBD may significantly inhibit CYP2C19. With the increasing use of marijuana and cannabis products, clinical studies are needed in order to determine the effects of other drugs on pharmacokinetics and pharmacodynamics.
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Affiliation(s)
- Gail D Anderson
- Department of Pharmacy, Box 357630, University of Washington, Seattle, WA, 98195, USA.
| | - Lingtak-Neander Chan
- Department of Pharmacy, Box 357630, University of Washington, Seattle, WA, 98195, USA
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Soyster P, Anzai NE, Fromont SC, Prochaska JJ. Correlates of nicotine withdrawal severity in smokers during a smoke-free psychiatric hospitalization. Prev Med 2016; 92:176-182. [PMID: 26892910 PMCID: PMC5108455 DOI: 10.1016/j.ypmed.2016.01.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 10/22/2022]
Abstract
Psychiatric hospitals are increasingly adopting smoke-free policies. Tobacco use is common among persons with mental illness, and nicotine withdrawal (NW), which includes symptoms of depression, anxiety, anger/irritability, and sleep disturbance, may confound psychiatric assessment and treatment in the inpatient setting. This study aimed to characterize NW and correlates of NW severity in a sample of smokers hospitalized for treatment of mental illness in California. Participants (N=754) were enrolled between 2009 and 2013, and averaged 17 (SD=10) cigarettes/day prior to hospitalization. Though most (70%) received nicotine replacement therapy (NRT) during hospitalization, a majority (65%) reported experiencing moderate to severe NW. In a general linear regression model, NW symptoms were more severe for women, African American patients, and polysubstance abusers. Though invariant by psychiatric diagnostic category, greater NW was associated with more severe overall psychopathology and greater cigarette dependence. The full model explained 46% of the total variation in NW symptom severity (F [19, 470]=23.03 p<0.001). A minority of participants (13%) refused NRT during hospitalization. Those who refused NRT reported milder cigarette dependence and stated no prior use of NRT. Among smokers hospitalized for mental illness, NW severity appears multidetermined, related to cigarette dependence, demographic variables, psychiatric symptom severity, and other substance use. Assessment and treatment of NW in the psychiatric hospital is clinically warranted and with extra attention to groups that may be more vulnerable or naïve to cessation pharmacotherapy.
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Affiliation(s)
- Peter Soyster
- University of California, Berkeley, Department of Psychology. Room 3210, Tolman Hall #1650, Berkeley, CA 94720, USA.
| | - Nicole E Anzai
- Stanford Prevention Research Center, Department of Medicine, Stanford University. 1265 Welch Road, Palo Alto, CA 94305, USA.
| | - Sebastien C Fromont
- Affiliated with Alta Bates Medical Center at the time the study was conducted. 2001 Dwight Way, Berkeley, CA 94704, USA
| | - Judith J Prochaska
- Stanford Prevention Research Center, Department of Medicine, Stanford University. 1265 Welch Road, Palo Alto, CA 94305, USA.
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The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. Psychopharmacology (Berl) 2016; 233:741-50. [PMID: 26626327 DOI: 10.1007/s00213-015-4161-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 10/24/2015] [Indexed: 10/22/2022]
Abstract
RATIONALE New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC). OBJECTIVES This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine. METHODS MEDLINE, Embase, and the Cochrane Library were searched with the search terms "clozapine" and "fluvoxamine" without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively. RESULTS Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence (A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine (B) but not agranulocytosis risk (B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used (C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis (D) or to reduce the effects of smoking on clozapine plasma levels (D). CONCLUSIONS Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications.
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Polat A, Çakir U, Gündüz N. Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia. Noro Psikiyatr Ars 2016; 53:87-88. [PMID: 28360774 DOI: 10.5152/npa.2015.9855] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 10/20/2014] [Indexed: 11/22/2022] Open
Abstract
Clozapine is an atypical antipsychotic drug that is approved by the US Food and Drug Administration (FDA) for the treatment of psychotic disorders. Agranulocytosis is a well-established side effect of clozapine; clozapine has also been associated with other blood dyscrasias like leukocytosis, albeit rarely. In this paper, we aim to report a case of possible clozapine-associated leukocytosis in a 41-year-old woman.
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Affiliation(s)
- Aslıhan Polat
- Department of Psychiatry, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Uğur Çakir
- Department of Psychiatry, Abant İzzet Baysal University School of Medicine, Bolu, Turkey
| | - Nermin Gündüz
- Department of Psychiatry, Kocaeli University School of Medicine, Kocaeli, Turkey
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Arranz MJ, Gallego C, Salazar J, Arias B. Pharmacogenetic studies of drug response in schizophrenia. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2016. [DOI: 10.1080/23808993.2016.1140554] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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de Brito RB, de Carvalho Araújo L, Diniz MJA, de Castro Georg R, Nabout JC, Vianelo RP, da Silva Santos R, da Silva Cruz AH, Ghedini PC. The CYP1A2 -163C > A polymorphism is associated with super-refractory schizophrenia. Schizophr Res 2015; 169:502-503. [PMID: 26530626 DOI: 10.1016/j.schres.2015.10.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/04/2015] [Accepted: 10/09/2015] [Indexed: 11/30/2022]
Affiliation(s)
- Rodrigo Bernini de Brito
- Post-Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil; Brain Institute, Bueno Medical Center, Goiânia, GO, Brazil
| | | | | | - Raphaela de Castro Georg
- Post-Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | | | - Rosana Pereira Vianelo
- Post-Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Rodrigo da Silva Santos
- Post-Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Aline Helena da Silva Cruz
- Post-Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Paulo César Ghedini
- Post-Graduate Program in Biological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil.
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Returning to tricyclic antidepressants for depression during childbearing: clinical and dosing challenges. Arch Womens Ment Health 2014; 17:239-46. [PMID: 24668283 PMCID: PMC4116330 DOI: 10.1007/s00737-014-0421-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 03/02/2014] [Indexed: 10/25/2022]
Abstract
Managing depression and anxiety during pregnancy and the postpartum period is challenging. Both pharmacological treatment and the lack thereof can pose threats to a fetus. SSRIs are the drugs of choice for use during pregnancy, but there is considerable evidence for the safety and efficacy of older antidepressants during pregnancy as well. This study highlights a single case of the use of the tricyclic nortriptyline during pregnancy and postpartum. The subject involved had an unexpectedly high ratio of serum level to drug dose during the postpartum period. We monitored the subject for a significantly greater portion of the postpartum period than has been done in previous studies, and explored medical and lifestyle changes that could account for the level-to-dose ratios we observed. Differences in smoking patterns, coupled with the patient's status as a genetic poor metabolizer, were the most likely explanations.
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Müller DJ, Kekin I, Kao ACC, Brandl EJ. Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. Int Rev Psychiatry 2013; 25:554-71. [PMID: 24151801 DOI: 10.3109/09540261.2013.838944] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Genetic testing may help to improve treatment outcomes in order to avoid non-response or severe side effects to psychotropic medication. Most robust data have been obtained for gene variants in CYP2D6 and CYP2C19 enzymes for antipsychotics and antidepressant treatment. We reviewed original articles indexed in PubMed from 2008-2013 on CYP2D6 and CYP2C19 gene variants and treatment outcome to antidepressant or antipsychotic medication. We have started providing CYP2D6 and CYP2C19 genotype information to physicians and conducted a survey where preliminary results are reported. Studies provided mixed results regarding the impact of CYP2D6 and CYP2C19 gene variation on treatment response. Plasma levels were mostly found associated with CYP metabolizer status. Higher occurrence/severity of side effects were reported in non-extensive CYP2D6 or CYP2C19 metabolizers. Results showed that providing genotypic information is feasible and generally well accepted by both patients and physicians. Although currently available studies are limited by small sample sizes and infrequent plasma drug level assessment, research to date indicates that CYP2D6 and CYP2C19 testing may be beneficial particularly for non-extensive metabolizing patients. In summary, clinical assessment of CYP2D6 and CYP2C19 metabolizer status is feasible, well accepted and optimizes drug treatment in psychiatry.
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Affiliation(s)
- Daniel J Müller
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto, Ontario , Canada
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Li W, Zeng S, Yu LS, Zhou Q. Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management. Ther Clin Risk Manag 2013; 9:259-71. [PMID: 23745048 PMCID: PMC3671798 DOI: 10.2147/tcrm.s43151] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Omeprazole, a proton pump inhibitor (PPI), is widely used for the treatment of dyspepsia, peptic ulcer, gastroesophageal reflux disease, and functional dyspepsia. Polypharmacy is common in patients receiving omeprazole. Drug toxicity and treatment failure resulting from inappropriate combination therapy with omeprazole have been reported sporadically. Systematic review has not been available to address the pharmacokinetic drug-drug interaction (DDI) profile of omeprazole with adverse consequences, the factors determining the degree of DDI between omeprazole and comedication, and the corresponding clinical risk management. METHODS Literature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed. RESULTS Omeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, nelfinavir, atazanavir, rilpivirine, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation. Meanwhile, low efficacy of omeprazole treatment would be anticipated, as omeprazole elimination could be significantly induced by comedicated efavirenz and herb medicines such as St John's wort, Ginkgo biloba, and yin zhi huang. The mechanism for DDI involves induction or inhibition of cytochrome P450, inhibition of P-glycoprotein or breast cancer resistance protein-mediated drug transport, and inhibition of oral absorption by gastric acid suppression. Sometimes, DDIs of omeprazole do not exhibit a PPI class effect. Other suitable PPIs or histamine 2 antagonists may be therapeutic alternatives that can be used to avoid adverse consequences. The degree of DDIs associated with omeprazole and clinical outcomes depend on factors such as genotype status of CYP2C19 and CYP1A2, ethnicity, dose and treatment course of precipitant omeprazole, pharmaceutical formulation of object drug (eg, mycophenolate mofetil versus enteric-coated mycophenolate sodium), other concomitant medication (eg, omeprazole-indinavir versus omeprazole-indinavir-ritonavir), and administration schedule (eg, intensified dosing of mycophenolate mofetil versus standard dosing). CONCLUSION Despite the fact that omeprazole is one of the most widely prescribed drugs internationally, clinical professionals should enhance clinical risk management on adverse DDIs associated with omeprazole and ensure safe combination use of omeprazole by rationally prescribing alternatives, checking the appropriateness of physician orders before dispensing, and performing therapeutic drug monitoring.
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Affiliation(s)
- Wei Li
- Division of Medical Affairs, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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Pharmacogenetics of CYP1A2 activity and inducibility in smokers and exsmokers. Pharmacogenet Genomics 2013; 23:286-92. [DOI: 10.1097/fpc.0b013e3283602e75] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Ferrari M, Bolla E, Bortolaso P, Callegari C, Poloni N, Lecchini S, Vender S, Marino F, Cosentino M. Association between CYP1A2 polymorphisms and clozapine-induced adverse reactions in patients with schizophrenia. Psychiatry Res 2012; 200:1014-7. [PMID: 22901441 DOI: 10.1016/j.psychres.2012.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 07/01/2012] [Accepted: 07/04/2012] [Indexed: 11/16/2022]
Abstract
We investigated the relationships between common polymorphisms in CYP1A2 (CYP1A2(⁎)1C and (⁎)1F), CYP1A2-mRNA levels in circulating lymphocytes and clozapine(CLZ)-induced adverse drug reactions (ADRs) in 34 patients. Patients with ADRs had a higher frequency of CYP1A2 low activity allele combinations (8/12; 67%) and lower CYP1A2-mRNA levels than patients without ADRs (6/22; 27%, P=0.019).
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Affiliation(s)
- Marco Ferrari
- Department of Clinical Medicine- Section Clinical and Experimental Pharmacology, University of Insubria, Via Otorino Rossi 9, 21100 Varese, Italy
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35
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Murray M. Cytochromes P450: Roles in the Biotransformation of Chemicals in Cigarette Smoke and Impact of Smoking Cessation on Concurrent Drug Therapy. J Smok Cessat 2012. [DOI: 10.1375/jsc.5.2.107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
AbstractCigarette smoke contains polycyclic aromatic hydrocarbons (PAHs) that activate the expression of cytochrome P450 family 1 (CYP1) enzymes in liver and other tissues; this process is dependent on the aryl hydrocarbon receptor (AhR) transcription factor. An important CYP1 enzyme, CYP1A2, has a critical role in the oxidation of drugs such as clozapine, olanzapine and theophylline; these drugs exhibit a high incidence of adverse effects that are linked to plasma concentrations. This article reviews the impact of smoking and smoking cessation on therapy with toxic drugs that undergo CYP-mediated elimination. PAHs in cigarette smoke activate the AhR and upregulate CYP1A2, which enhances the clearance of these drugs, diminishes their efficacy and necessitates the use of higher doses. However, smoking cessation decreases PAH exposure, which leads to a decline in clearance of CYP1A2 substrate drugs. Dose reductions and close therapeutic monitoring for such drugs are recommended in patients who cease smoking.
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Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking. Pharmacogenet Genomics 2012; 22:143-51. [DOI: 10.1097/fpc.0b013e32834e9e1a] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Plowchalk DR, Rowland Yeo K. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. Eur J Clin Pharmacol 2012; 68:951-60. [PMID: 22258279 DOI: 10.1007/s00228-011-1189-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 11/24/2011] [Indexed: 11/26/2022]
Abstract
PURPOSE To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers. METHODS Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro-in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non-smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2. RESULTS Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94 pmol/mg microsomal protein for subjects smoking 0, 1-5, 6-10, 11-20, and >20 cigarettes/day respectively. Predicted -fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non-smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90 L/h (40%) and 141 L/h (34%) respectively, and 100 L/h (58%) and 131 L/h (33%) respectively. CONCLUSIONS This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach.
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Affiliation(s)
- David R Plowchalk
- Clinical Pharmacology, Primary Care BU, Pfizer Inc., 445 Eastern Point Road, Groton, CT 06340, USA.
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Abstract
As a consequence of individualized antipsychotic pharmacotherapy, many patients need more than a single drug, since they do not respond sufficiently to monotherapy. Other patients suffer from comorbid diseases and therefore require additional drugs from other pharmacological classes. Drug combinations, however, can give rise to pharmacokinetic and/or pharmacodynamic drug-drug interactions. Evaluation of pharmacokinetic interactions with antipsychotic drugs must consider substrate, inhibitor, and inducer properties for the cytochrome P450 (CYP) isoenzymes of all combined drugs. For consideration of pharmacodynamic interactions, special attention must be given to effects on dopamine D(2), histamine H(1), and acetylcholine M(1) receptors and on cardiac potassium channels. Additive pharmacological actions of combined drugs on these target structures can induce adverse reactions such as extrapyramidal symptoms, drowsiness, metabolic disturbances leading to weight gain and cardiac problems, cognitive impairment, delirium, or ventricular arrhythmia. Measuring plasma concentrations, i.e., therapeutic drug monitoring (TDM), is valuable to adjust antipsychotic medication when drug combinations contain inhibitors or inducers that alter plasma concentrations of the antipsychotic drugs. Amalgamating the broad knowledge on drug-drug interactions and using appropriately the option to monitor plasma concentrations in blood will help to apply complex combination therapies with antipsychotic drugs with maximal efficiency and safety.
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Affiliation(s)
- Christoph Hiemke
- Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany.
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Yousefi MK, Folsom TD, Fatemi SH. A Review of Varenicline's Efficacy and Tolerability in Smoking Cessation Studies in Subjects with Schizophrenia. ACTA ACUST UNITED AC 2012; S4. [PMID: 22514788 DOI: 10.4172/2155-6105.s4-001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Schizophrenia is a severe psychiatric disorder affecting 1% of the world's population. Nicotine addiction is one of the most important health concerns for patients with schizophrenia. An extensive body of evidence points to a high prevalence rate of comorbid nicotine addiction in people with schizophrenia (70-90%), which contributes to significant cardiovascular and cancer risks in this vulnerable population. Therefore, effective smoking cessation strategies could play a major role in preventing significant morbidity and mortality in this population. Two of the most common pharmacological approaches to smoking cessation, bupropion and nicotine replacement therapy (NRT), have been used in psychiatric patients to reduce their smoking. In 2006, varenicline, a partial agonist of α4β2 acetylcholine receptor, was approved for smoking cessation by the FDA. This drug not only has the beneficial effects on withdrawal symptoms, but also reduces craving and rewarding effects of smoking. While varenicline has been shown to be an effective, safe medication for the general population, its efficacy and safety for subjects with schizophrenia is less well characterized. A number of case studies have prompted FDA warnings about the potential exacerbation of psychiatric symptoms. However, other case studies and pilot studies have shown varenicline to be a safe and effective treatment for smoking cessation in subjects with schizophrenia. Varenicline has the potential to reduce smoking in subjects with schizophrenia, however, clinicians should carefully monitor patients receiving varenicline for potential exacerbation of psychiatric symptoms.
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Affiliation(s)
- Mahtab Karkhane Yousefi
- Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, USA
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Impact of Smoking, Smoking Cessation, and Genetic Polymorphisms on CYP1A2 Activity and Inducibility. Clin Pharmacol Ther 2011; 90:117-25. [PMID: 21593735 DOI: 10.1038/clpt.2011.70] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Bersani FS, Capra E, Minichino A, Pannese R, Girardi N, Marini I, Delle Chiaie R, Biondi M. Factors affecting interindividual differences in clozapine response: a review and case report. Hum Psychopharmacol 2011; 26:177-87. [PMID: 21455971 DOI: 10.1002/hup.1191] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Clozapine is the most powerful new‐generation antipsychotic. Although this drug leads to great therapeutic benefits, two types of undesirable conditions frequently occur with its use: side effects and resistance to treatment. Therapeutic drug monitoring of clozapine would be very useful to avoid both these situations. The necessity of monitoring the therapy is the result of a wide interindividual variability in the metabolism of clozapine. In this review, we highlight all the conditions underlying this variability, analyzing them one by one. METHODS Relevant literature was identified through a search of MEDLINE and PubMed. In addition, the case of a treatment‐resistant patient with accelerated metabolism of clozapine is reported as representative of utility of therapeutic drug monitoring in terms of clozapine dose adjustment. RESULTS Genetic polymorphisms of cytochrome P450 enzymes and of neurotransmitter receptors; drug interactions; interactions of clozapine with other substances such as food and drink; smoking; and nonmodifiable variables such as age, ethnicity, and gender have been examined in relation to the existing scientific literature. The laboratory techniques that clinicians could use to identify these variables and adequate therapies are also reviewed.
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A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine. Acta Psychiatr Scand 2010; 121:393-7. [PMID: 19824991 DOI: 10.1111/j.1600-0447.2009.01482.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To investigate the effect of a complete smoking ban on a group of psychiatric inpatients maintained on the antipsychotic medication clozapine. METHOD Retrospective data on clozapine dose and plasma levels were collected from a three month period before and a six month period after the introduction of the smoking ban. RESULTS Before the ban only 4.2% of patients who smoked had a plasma clozapine level > or =1000 microg/l but after the ban this increased to 41.7% of the sample within the six month period following the ban despite dose reductions. CONCLUSION Abrupt cessation of smoking is associated with a potentially serious risk of toxicity in patients taking clozapine. Plasma clozapine levels must be monitored closely and adjustments made in dosage, if necessary, for at least six months after cessation.
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Abstract
INTRODUCTION The prevalence of smoking is high in persons with serious mental illness (SMI) despite associated health risks. Persons with SMI die on average 25 years earlier than the general population and an increased focus on wellness, including smoking cessation, has been a goal of federal, state, and municipal governments. OBJECTIVES The primary objective of this study was to evaluate the effects of smoking cessation on symptom severity in psychiatric inpatients at a New York State psychiatric facility 1 year after a smoke-free policy had been implemented. The secondary objective of this study was to evaluate cardiometabolic risk factors. METHODS A retrospective chart review of 26 adult psychiatric inpatients receiving either clozapine, olanzapine, or both at any time between January 2006 and December 2007 was conducted. In addition to Brief Psychiatric Rating Scale (BPRS) scores and cardiometabolic measures (body weight, body mass index [BMI], and blood pressures before and after implementation of the smoke-free policy), other information collected included age, gender, diagnosis, the frequency of psychiatric medications used on an as-needed (p.r.n.) basis, immediate-need (stat) medication use, medication dosing, number of psychiatric emergencies, Global Assessment of Functioning (GAF) scores, privilege status, and time in special observation. Patients were compared on their own pre- and post-smoking cessation parameters and data were analyzed using a dependent t-test with p < 0.01 chosen as indicating significance. RESULTS Data analysis revealed a small but statistically significant decrease in GAF scores (p < 0.01), but no other significant difference between values pre- and post-smoking cessation. CONCLUSION Analysis demonstrated no change in psychiatric symptomatology or cardiometabolic factors 1 year post-smoking cessation in individuals with schizophrenia taking clozapine, olanzapine, or both. Further investigation is needed before concluding that smoking cessation has no impact on symptoms or on cardiometabolic risk factors. Despite a slight but statistically significant worsening in GAF scores, the health benefits of smoking cessation should continue to form the basis of encouraging smoking cessation in persons with SMI while longer term and methodologically more rigorous assessments on psychiatric and general health status are undertaken.
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Lohoff FW, Ferraro TN. Pharmacogenetic considerations in the treatment of psychiatric disorders. Expert Opin Pharmacother 2010; 11:423-39. [DOI: 10.1517/14656560903508762] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. Arh Hig Rada Toksikol 2009; 60:217-42. [PMID: 19581216 DOI: 10.2478/10004-1254-60-2009-1885] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.
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Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study. Ther Drug Monit 2009; 31:360-6. [PMID: 19349931 DOI: 10.1097/ftd.0b013e31819c7037] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean +/- SD age, 38 +/- 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg.The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine, smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form.The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring.
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Guo L, Dong Z, Guthrie H. Validation of a guinea pig Langendorff heart model for assessing potential cardiovascular liability of drug candidates. J Pharmacol Toxicol Methods 2009; 60:130-51. [DOI: 10.1016/j.vascn.2009.07.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Accepted: 07/06/2009] [Indexed: 02/02/2023]
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Schaffer SD, Yoon S, Zadezensky I. A review of smoking cessation: potentially risky effects on prescribed medications. J Clin Nurs 2009; 18:1533-40. [PMID: 19490292 DOI: 10.1111/j.1365-2702.2008.02724.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS AND OBJECTIVES To identify prescription drugs that require dosage adjustment or monitoring in patients who quit smoking and to provide recommendations for dosage adjustment based on available evidence. BACKGROUND Health care providers are urged to facilitate smoking cessation for patients who smoke, but the effects of smoking cessation on the metabolism of some drugs is not routinely considered. DESIGN A comprehensive literature review. METHODS The review was conducted in 2008 using a computerised drug interaction program and multiple PubMed and CINAHL searches to identify prescription drugs with clinically significant pharmacokinetic or pharmacodynamic changes caused by smoking cessation. RESULTS Although much of the evidence is case report, dosage adjustments are clearly indicated for warfarin, olanzapine, clozapine and theophylline since they are metabolised by cytochrome P450 CYP1A2 and also have narrow therapeutic ratios. Careful monitoring is recommended for other CYP1A2 metabolised drugs, including those for hypertension and Alzheimer's disease. For many affected drugs, smoking cessation reverses smoking-induced CYP1A2 hepatic enzyme levels to normal, increasing plasma concentrations in patients whose dose was established while smoking. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, nicotine replacement will not alter the effect. CONCLUSIONS The effects of smoking cessation on drugs metabolised by CYP1A2 have been under-appreciated by health care providers. Smoking cessation may increase plasma levels of some drugs to potentially toxic levels. Further research is warranted to clarify this effect. RELEVANCE TO CLINICAL PRACTICE When patients stop smoking, providers should carefully review prescribed drug regimens and adjust or monitor drugs whose metabolism is affected by smoking cessation. This is particularly important for patients who abruptly stop smoking due to hospitalisation and for older patients who are likely to be taking multiple medications.
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Affiliation(s)
- Susan D Schaffer
- University of Florida College of Nursing, Gainesville, FL32610-0187, USA
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Abstract
To examine the genetic factors influencing clozapine kinetics in vivo, 75 patients treated with clozapine were genotyped for CYPs and ABCB1 polymorphisms and phenotyped for CYP1A2 and CYP3A activity. CYP1A2 activity and dose-corrected trough steady-state plasma concentrations of clozapine correlated significantly (r = -0.61; P = 1 x 10), with no influence of the CYP1A2*1F genotype (P = 0.38). CYP2C19 poor metabolizers (*2/*2 genotype) had 2.3-fold higher (P = 0.036) clozapine concentrations than the extensive metabolizers (non-*2/*2). In patients comedicated with fluvoxamine, a strong CYP1A2 inhibitor, clozapine and norclozapine concentrations correlate with CYP3A activity (r = 0.44, P = 0.075; r = 0.63, P = 0.007, respectively). Carriers of the ABCB1 3435TT genotype had a 1.6-fold higher clozapine plasma concentrations than noncarriers (P = 0.046). In conclusion, this study has shown for the first time a significant in vivo role of CYP2C19 and the P-gp transporter in the pharmacokinetics of clozapine. CYP1A2 is the main CYP isoform involved in clozapine metabolism, with CYP2C19 contributing moderately, and CYP3A4 contributing only in patients with reduced CYP1A2 activity. In addition, ABCB1, but not CYP2B6, CYP2C9, CYP2D6, CYP3A5, nor CYP3A7 polymorphisms, influence clozapine pharmacokinetics.
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