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Kirubakaran R, Singh RM, Carland JE, Day RO, Stocker SL. Evaluation of Published Population Pharmacokinetic Models to Inform Tacrolimus Therapy in Adult Lung Transplant Recipients. Ther Drug Monit 2024; 46:434-445. [PMID: 38723160 DOI: 10.1097/ftd.0000000000001210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/15/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND The applicability of currently available tacrolimus population pharmacokinetic models in guiding dosing for lung transplant recipients is unclear. In this study, the predictive performance of relevant tacrolimus population pharmacokinetic models was evaluated for adult lung transplant recipients. METHODS Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero. RESULTS In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33). CONCLUSIONS Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.
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Affiliation(s)
- Ranita Kirubakaran
- School of Clinical Medicine, St. Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
- Department of Pharmacy, Ministry of Health, Putrajaya, Malaysia
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Rani M Singh
- School of Clinical Medicine, St. Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
| | - Jane E Carland
- School of Clinical Medicine, St. Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
| | - Richard O Day
- School of Clinical Medicine, St. Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
| | - Sophie L Stocker
- School of Clinical Medicine, St. Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Sydney Institute for Infectious Diseases, University of Sydney, Sydney, NSW, Australia ; and
- Sydney Musculoskeletal Health, University of Sydney, Sydney, NSW, Australia
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Second and Third Generational Advances in Therapies of the Immune-Mediated Kidney Diseases in Children and Adolescents. CHILDREN 2022; 9:children9040536. [PMID: 35455580 PMCID: PMC9030090 DOI: 10.3390/children9040536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 11/17/2022]
Abstract
Therapy of immune-mediated kidney diseases has evolved during recent decades from the non-specific use of corticosteroids and antiproliferative agents (like cyclophosphamide or azathioprine), towards the use of more specific drugs with measurable pharmacokinetics, like calcineurin inhibitors (cyclosporine A and tacrolimus) and mycophenolate mofetil, to the treatment with biologic drugs targeting detailed specific receptors, like rituximab, eculizumab or abatacept. Moreover, the data coming from a molecular science revealed that several drugs, which have been previously used exclusively to modify the upregulated adaptive immune system, may also exert a local effect on the kidney microstructure and ameliorate the functional instability of podocytes, reducing the leak of protein into the urinary space. The innate immune system also became a target of new therapies, as its specific role in different kidney diseases has been de novo defined. Current therapy of several immune kidney diseases may now be personalized, based on the detailed diagnostic procedures, including molecular tests. However, in most cases there is still a space for standard therapies based on variable protocols including usage of steroids with the steroid-sparing agents. They are used as a first-line treatment, while modern biologic agents are selected as further steps in cases of lack of the efficacy or toxicity of the basic therapies. In several clinical settings, the biologic drugs are effective as the add-on therapy.
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