Optimizing Dose Conversion From IR-Tac to LCP-Tac Formulations in Renal Transplant Recipients: A Population Pharmacokinetic Modeling Study

Background/Objectives: The extended-release once-daily tacrolimus (LCP-Tac) formulation demonstrates enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Switching from IR-Tac to LCP-Tac is emerging as a viable immunosuppressive strategy in clinical settings. This study aimed to examine the influence of genetics and other covariates on the general conversion ratio of 1:0.7. Methods: A population pharmacokinetic model was developed using rich sampling data from 30 stable renal transplant patients who received both IR-TAC and LCP-TAC formulations. Results: The pharmacokinetic (PK) profile was best described by a two-compartment model with first-order absorption and linear elimination for both formulations. The model effectively captured differences in the absorption phases of the two formulations by estimating distinct absorption rate constants and lag times. It also accounted for circadian rhythm effects on apparent elimination clearance and absorption rate constants for IR-Tac. A key finding was the significant impact of the CYP3A5 genetic polymorphism on apparent clearance and the dose conversion rate from IR-Tac to LCP-Tac. CYP3A5*1 expressers had higher clearance and achieved lower exposure with the same IR-Tac dose regimen compared to non-expressers. Conclusion: The enhanced oral bioavailability of LCP-Tac necessitates dose reductions across the patient cohort following conversion from IR-Tac. However, CYP3A5*1 expressers require a more pronounced reduction (1:0.6 conversion ratio) compared to non-expressers (1:0.7) to maintain steady-state concentrations achieved initially with IR-Tac.