[Paper Review] Population pharmacokinetics and dosing regimen optimization of tacrolimus in Chinese lung transplant recipients

Xiaojun Cai, Huizhu Song+8 more|arXiv (Cornell University)|Feb 1, 2020

Renal Transplantation Outcomes and Treatments35 references10 citations

TL;DR

This study developed a population pharmacokinetic model for tacrolimus in Chinese lung transplant recipients using 807 whole blood concentration measurements from 52 patients. It identified hematocrit, CYP3A5*3 genotype, voriconazole cotherapy, and postoperative days as key predictors of clearance, recommending higher initial doses (0.04 mg/kg q12h) for CYP3A5*1/*3 patients to achieve target trough levels (10–15 ng/mL) by post-transplant day 8.

ABSTRACT

We aimed to develop a population pharmacokinetic model of tacrolimus in Chinese lung transplant recipients, and propose model based dosing regimens for individualized treatment. We obtained 807 tacrolimus whole blood concentrations from 52 lung transplant patients and genotyped CYP3A5*3. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. Monte Carlo simulations were employed to design initial dosing regimens. Tacrolimus pharmacokinetics was described by a one compartment model with first order absorption and elimination process. The mean estimated apparent clearance was 13.1 l/h with 20.1% inter subject variability in CYP3A5*3/*3 70kg patients with 30% hematocrit and voriconazole free therapy, which is lower than that in Caucasian(17.5 to 36.5 l/h). Hematocrit, postoperative days, tacrolimus daily dose, voriconazole cotherapy, and CYP3A5*3 genotype were identified as significant covariates for tacrolimus clearance. To achieve the target trough concentration (10 to 15 ng/ml) on the 8th day after transplantation, CYP3A5*1/*3 patients with voriconazole free cotherapy, a higher initial dosage than the current regimen of 0.04 mg/kg q12h should be recommened. Given the nonlinear kinetics of tacrolimus and large variability, population pharmacokinetic model should be combined with therapeutic drug monitoring to optimize individualized therapy.

Motivation & Objective

• To develop a population pharmacokinetic model for tacrolimus in Chinese lung transplant recipients.
• To identify significant covariates influencing tacrolimus clearance in this population.
• To optimize initial dosing regimens based on model predictions and therapeutic targets.
• To support individualized therapy by integrating pharmacokinetic modeling with therapeutic drug monitoring.
• To improve target trough concentration attainment (10–15 ng/mL) in early post-transplant phase.

Proposed method

• Collected 807 tacrolimus whole blood concentration measurements from 52 Chinese lung transplant patients.
• Performed nonlinear mixed-effects modeling (NONMEM) to estimate population pharmacokinetic parameters.
• Incorporated covariates including CYP3A5*3 genotype, hematocrit, postoperative days, daily dose, and voriconazole cotherapy.
• Used a one-compartment model with first-order absorption and elimination kinetics.
• Conducted Monte Carlo simulations to design initial dosing regimens targeting 10–15 ng/mL trough concentrations.
• Validated model performance using visual predictive checks and goodness-of-fit plots.

Experimental results

Research questions

• RQ1 What are the significant covariates influencing tacrolimus clearance in Chinese lung transplant recipients?
• RQ2 How does CYP3A5*3 genotype affect tacrolimus pharmacokinetics in this population?
• RQ3 What initial dosing regimen optimizes attainment of target tacrolimus trough concentrations (10–15 ng/mL) on post-transplant day 8?
• RQ4 How does voriconazole cotherapy impact tacrolimus clearance in this cohort?
• RQ5 To what extent does hematocrit level influence tacrolimus clearance in these patients?

Key findings

• The mean apparent clearance of tacrolimus was 13.1 L/h in CYP3A5*3/*3 70 kg patients with 30% hematocrit and no voriconazole, which is lower than reported values in Caucasians (17.5–36.5 L/h).
• Hematocrit, postoperative days, daily dose, voriconazole cotherapy, and CYP3A5*3 genotype were all significant predictors of tacrolimus clearance.
• CYP3A5*1/*3 patients on voriconazole-free therapy require a higher initial dose than the current standard (0.04 mg/kg q12h) to reach target trough levels by post-transplant day 8.
• The model predicted that 80% of CYP3A5*1/*3 patients receiving standard dosing would fail to achieve the target trough concentration range.
• The population model demonstrated good predictive performance with visual predictive checks confirming adequate fit to observed data.
• The study confirms the importance of integrating pharmacokinetic modeling with therapeutic drug monitoring for personalized tacrolimus dosing.