Population pharmacokinetics and dosage optimisation of tacrolimus coadministration with Wuzhi capsule in adult liver transplant patients

Abstract

1. This study aimed to establish a population pharmacokinetic model of tacrolimus coadministration with Wuzhi capsule and optimise the dosage regimen in adult liver transplant patients.

2. Totally 1327 tacrolimus trough concentrations from 116 adult liver transplant patients were obtained for model development. A one-compartment model with first-order absorption and elimination was used to analyse the data, and the final model was internally verified using a goodness-of-fit diagnostic plot, bootstrap methods, and visual prediction test. A total of 29 patients with 250 tacrolimus trough concentrations were used for external validation via prediction-based diagnostics. Additionally, the simulation was used to optimise the recommended dose of tacrolimus and Wuzhi capsules.

3. The estimated apparent clearance and volume of the distribution of tacrolimus were 15.4 L/h and 1210 L, respectively. The tacrolimus daily dose, Wuzhi capsule daily dose, postoperative time, alanine transaminase, haemoglobin, total bilirubin, direct bilirubin, estimated glomerular filtration rate, and urea, concomitant with voriconazole and fluconazole, were identified as significant covariates affecting the pharmacokinetic parameters. Internal and external validation showed that the final model was stable and reliable for predicting performance.

4. The final model could provide guidance for dosage optimisation of tacrolimus coadministered with Wuzhi capsules in adult liver transplantation patients.

Keywords:

• Tacrolimus
• Wuzhi capsule
• population pharmacokinetics
• adult liver transplantation
• dosage optimisation

Disclosure statement

The authors report no declarations of interest.

Data availability statement

The data analysed and the control file of PPK in this study are available from the corresponding author under reasonable request.

Additional information

Funding

This work was supported by Jiangsu Provincial Medical Youth Talents Project (No. QNRC2016013) and Nanjing Medical Science and Technique Development Foundation (No. YKK17075).