Zeyar Mohammed Ali, Beatriz Fernández-Alarcón, Pere Fontova, Anna Vidal-Alabró, Raul Rigo-Bonnin, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alexandre Favà, Josep M Grinyó, Josep M Cruzado, Helena Colom, Nuria Lloberas
{"title":"肾移植受者从IR-Tac到LCP-Tac的最佳剂量转换:群体药代动力学模型研究。","authors":"Zeyar Mohammed Ali, Beatriz Fernández-Alarcón, Pere Fontova, Anna Vidal-Alabró, Raul Rigo-Bonnin, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alexandre Favà, Josep M Grinyó, Josep M Cruzado, Helena Colom, Nuria Lloberas","doi":"10.3390/pharmaceutics17091185","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background/Objectives</b>: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general conversion ratio of 1:0.7 is widely recommended when switching between formulations, current guidelines do not account for pharmacogenetic variability. This study aimed to determine whether CYP3A5 genotype influences the conversion ratio in Caucasian renal transplant recipients using population pharmacokinetic (PopPK) modeling. <b>Methods</b>: A PopPK model was developed in NONMEM using full PK profiles (10-18 samples per patient) from 30 stable renal transplant patients treated with both IR-Tac and LCP-Tac. <b>Results</b>: Tacrolimus pharmacokinetics were best described by a two-compartment model with first-order absorption and linear elimination with distinct absorption rate constants and lag times for each formulation. Including circadian rhythm in the apparent clearance (CL/F) and Ka of IR-Tac significantly improved the model. CYP3A5 polymorphism was the most powerful covariate explaining variability on CL/F. <i>CYP3A5*1</i> expressers showed higher clearance and lower exposure requiring a more pronounced dose reduction upon conversion to LCP-Tac. Simulations indicated optimal conversion ratios of 1:0.6 for <i>CYP3A5*1</i> expressers and 1:0.7 for non-expressers. <b>Conclusions</b>: These findings highlight the need to move beyond a one-size-fits-all conversion ratio and adopt genotype-informed strategies. LCP-Tac's enhanced bioavailability requires dose reduction, greater in expressers when switching from IR-Tac. These genotype-specific recommendations provide clinically actionable guidance to complement therapeutic drug monitoring and support more individualized conversion protocols in renal transplantation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473248/pdf/","citationCount":"0","resultStr":"{\"title\":\"Optimizing Dose Conversion from IR-Tac to LCP-Tac Formulations in Renal Transplant Recipients: A Population Pharmacokinetic Modeling Study.\",\"authors\":\"Zeyar Mohammed Ali, Beatriz Fernández-Alarcón, Pere Fontova, Anna Vidal-Alabró, Raul Rigo-Bonnin, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alexandre Favà, Josep M Grinyó, Josep M Cruzado, Helena Colom, Nuria Lloberas\",\"doi\":\"10.3390/pharmaceutics17091185\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background/Objectives</b>: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general conversion ratio of 1:0.7 is widely recommended when switching between formulations, current guidelines do not account for pharmacogenetic variability. This study aimed to determine whether CYP3A5 genotype influences the conversion ratio in Caucasian renal transplant recipients using population pharmacokinetic (PopPK) modeling. <b>Methods</b>: A PopPK model was developed in NONMEM using full PK profiles (10-18 samples per patient) from 30 stable renal transplant patients treated with both IR-Tac and LCP-Tac. <b>Results</b>: Tacrolimus pharmacokinetics were best described by a two-compartment model with first-order absorption and linear elimination with distinct absorption rate constants and lag times for each formulation. Including circadian rhythm in the apparent clearance (CL/F) and Ka of IR-Tac significantly improved the model. CYP3A5 polymorphism was the most powerful covariate explaining variability on CL/F. <i>CYP3A5*1</i> expressers showed higher clearance and lower exposure requiring a more pronounced dose reduction upon conversion to LCP-Tac. Simulations indicated optimal conversion ratios of 1:0.6 for <i>CYP3A5*1</i> expressers and 1:0.7 for non-expressers. <b>Conclusions</b>: These findings highlight the need to move beyond a one-size-fits-all conversion ratio and adopt genotype-informed strategies. LCP-Tac's enhanced bioavailability requires dose reduction, greater in expressers when switching from IR-Tac. 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Optimizing Dose Conversion from IR-Tac to LCP-Tac Formulations in Renal Transplant Recipients: A Population Pharmacokinetic Modeling Study.
Background/Objectives: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general conversion ratio of 1:0.7 is widely recommended when switching between formulations, current guidelines do not account for pharmacogenetic variability. This study aimed to determine whether CYP3A5 genotype influences the conversion ratio in Caucasian renal transplant recipients using population pharmacokinetic (PopPK) modeling. Methods: A PopPK model was developed in NONMEM using full PK profiles (10-18 samples per patient) from 30 stable renal transplant patients treated with both IR-Tac and LCP-Tac. Results: Tacrolimus pharmacokinetics were best described by a two-compartment model with first-order absorption and linear elimination with distinct absorption rate constants and lag times for each formulation. Including circadian rhythm in the apparent clearance (CL/F) and Ka of IR-Tac significantly improved the model. CYP3A5 polymorphism was the most powerful covariate explaining variability on CL/F. CYP3A5*1 expressers showed higher clearance and lower exposure requiring a more pronounced dose reduction upon conversion to LCP-Tac. Simulations indicated optimal conversion ratios of 1:0.6 for CYP3A5*1 expressers and 1:0.7 for non-expressers. Conclusions: These findings highlight the need to move beyond a one-size-fits-all conversion ratio and adopt genotype-informed strategies. LCP-Tac's enhanced bioavailability requires dose reduction, greater in expressers when switching from IR-Tac. These genotype-specific recommendations provide clinically actionable guidance to complement therapeutic drug monitoring and support more individualized conversion protocols in renal transplantation.
PharmaceuticsPharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍:
Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications, and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.