Mohammed Ali, Z.; Meertens, M.; Fernández, B.; Fontova, P.; Vidal-Alabró, A.; Rigo-Bonnin, R.; Melilli, E.; Cruzado, J.M.; Grinyó, J.M.; Colom, H.; Lloberas, N. CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach. Pharmaceutics2023, 15, 2699.
Mohammed Ali, Z.; Meertens, M.; Fernández, B.; Fontova, P.; Vidal-Alabró, A.; Rigo-Bonnin, R.; Melilli, E.; Cruzado, J.M.; Grinyó, J.M.; Colom, H.; Lloberas, N. CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach. Pharmaceutics 2023, 15, 2699.
Mohammed Ali, Z.; Meertens, M.; Fernández, B.; Fontova, P.; Vidal-Alabró, A.; Rigo-Bonnin, R.; Melilli, E.; Cruzado, J.M.; Grinyó, J.M.; Colom, H.; Lloberas, N. CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach. Pharmaceutics2023, 15, 2699.
Mohammed Ali, Z.; Meertens, M.; Fernández, B.; Fontova, P.; Vidal-Alabró, A.; Rigo-Bonnin, R.; Melilli, E.; Cruzado, J.M.; Grinyó, J.M.; Colom, H.; Lloberas, N. CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach. Pharmaceutics 2023, 15, 2699.
Abstract
The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed using NONMEM v7.5, from full PK profiles from a clinical study (n=30) and trough concentrations (C0) from patient follow-up (n=68). The PK profile of the LCP-Tac formulation was best described by a two-compartment model with linear elimination, parameterised in elimination (CL/F) and distributional (CLD/F) clearances and central compartment (Vc/F) and peripheral compartment (Vp/F) distribution volumes. A time lagged first order absorption process was characterized using transit compartment models. According to the structural part of the base model, the LCP-Tac showed an absorption profile characterized by 2 transit compartments and a mean transit time of 3.02 hours. Inter-individual variability was associated with CL/F, Vc/F and Vp/F. Adding inter-occasion variability (IOV) on CL/F caused a statistically significant reduction in the model minimum objective function MOFV (p<0.001). Genetic polymorphism of CYP3A5 and cluster of CYP3A4/A5 SNPs statistically significantly influenced Tac CL/F. In conclusion a PopPK model was successfully developed for LCP-Tac formulation in stable renal transplant patients. CYP3A4/A5 SNPs as a combined cluster including three different phenotypes (high, intermediate, and poor metabolizers) was the most powerful covariate to describe part of inter-individual variability associated with apparent elimination clearance. Incorporating this covariate in the initial dose calculation and during the therapeutic drug monitoring (TDM) would probably optimize Tac exposure attainments.
Copyright:
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