Effect of drug combination on tacrolimus target dose in renal transplant patients with different CYP3A5 genotypes

Abstract

1. Various factors, including genetic polymorphisms, drug–drug interactions, and patient characteristics influence the blood concentrations of tacrolimus in renal transplant patients. In the present study, we established a population pharmacokinetic model to explore the effect of combined use of Wuzhi capsules/echinocandins and the patients’ biochemical parameters such as haematocrit on blood concentrations and target doses of tacrolimus in renal transplant patients with different CYP3A5 genotypes. The aim of the study was to propose an individualised tacrolimus administration regimen for early renal transplant recipients.

2. In this retrospective cohort study, we included 240 renal transplant recipients within 21 days of surgery (174 males and 66 females, mean age 39.4 years), who received tacrolimus alone (n = 54), in combination with Wuzhi capsules (99) or caspofungin (57) or micafungin (30). We collected demographic characteristics, clinical indicators, CYP3A5 genotypes, and 1950 steady-state concentrations of tacrolimus and included them in population pharmacokinetic model. An additional 110 renal transplant recipients and 625 steady-state concentrations of tacrolimus were included for external validation of the model. The population pharmacokinetic model was established and Monte Carlo was used to simulate probabilities for achieving the target concentration for individual tacrolimus administration.

3. A two-compartment model of first-order absorption and elimination was developed to describe the population pharmacokinetics of tacrolimus. CYP3A5 genotypes and co-administration of Wuzhi capsules, as well as time after renal transplantation and haematocrit, were important factors affecting the clearance of tacrolimus. We found no obvious change in trend in the scatter plot of tacrolimus clearance rate vs. haematocrit. The Monte Carlo simulation indicated the following recommended doses of tacrolimus alone: 0.14 mg⋅kg⁻¹⋅d⁻¹ for genotype CYP3A5*1*1, 0.12 mg⋅kg⁻¹⋅d⁻¹ for CYP3A5*1*3, and 0.10 mg⋅kg⁻¹⋅d⁻¹ for CYP3A5*3*3. For patients receiving the combination with Wuzhi capsules, the recommended doses of tacrolimus were 0.10 mg⋅kg⁻¹⋅d⁻¹ for CYP3A5*1*1, 0.08 mg⋅kg⁻¹⋅d⁻¹ for CYP3A5*1*3, and 0.06 mg⋅kg⁻¹⋅d⁻¹ for CYP3A5*3*3 genotypes. Caspofungin or micafungin had no effect on the clearance of tacrolimus in renal transplant recipients.

4. The population pharmacokinetics of tacrolimus in renal transplant patients was evaluated and the individual administration regimen of tacrolimus was simulated. For early kidney transplant recipients receiving tacrolimus treatment, not only body weight, but also CYP3A5 genotypes and drugs used in combination should be considered when determining the target dose of tacrolimus.

Keywords:

• Kidney transplant
• CYP3A5 genotype
• drug interaction
• population pharmacokinetics
• echinocandins
• Wuzhi capsule

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This work was supported by the National Key Research Project of Precision Special Medical Integrated Application and Demonstration System Construction [project no. 2017YFC0910004] and Jinan Science and Technology Bureau Project [project no. 201602171].