Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation

BACKGROUND: In order to improve the precision of treatment with tacrolimus in Chinese patients undergoing pediatric liver transplantation, the optimum initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics. METHODS: Demographic data, clinical parameters, drug combinations and pharmacogenomics were integrated to build a population pharmacokinetic model using NONMEM. Additionally, Monte Carlo simulations were used to optimize the recommended initial dose. RESULTS: Weight, patient cytochrome 450 3A (CYP3A)5 genotype, and co-administration with wuzhi-capsule (WZ) were incorporated into the final model. For children with a CYP3A5*3/*3 genotype not co-administered WZ, 0.10 mg/kg/day split into two doses was recommended for patients weighing 5–17 kg, and 0.05 mg/kg/day split into two doses was recommended for patients weighing 17–60 kg. For children with a CYP3A5*1 allele not co-administered WZ, 0.25 mg/kg/day for patients weighing 5–10 kg, 0.20 mg/kg/day for patients weighing 10–17 kg, 0.15 mg/kg/day for patients weighing 17–36 kg, and 0.10 mg/kg/day for patients weighing 36–60 kg; all split into two doses was recommended. For children with a CYP3A5*3/*3 genotype co-administered WZ, 0.10 mg/kg/day for patients weighing 5–11 kg, and 0.05 mg/kg/day for patients weighing 11–60 kg; both split into two doses was recommended. For children with a CYP3A5*1 allele who were co-administered WZ, 0.20 mg/kg/day for patients weighing 5–10 kg, 0.15 mg/kg/day for patients weighing 10–22 kg, and 0.10 mg/kg/day for patients weighing 22–60 kg all split into two doses was recommended. CONCLUSIONS: The optimal initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics in Chinese patients undergoing pediatric liver transplantation.