Dosing strategy of tacrolimus when co-administered with Wuzhi tablet in renal transplant recipients.

Abstract

Tacrolimus (TAC) is a first-line immunosuppressant to prevent allograft rejection. Wuzhi tablet is widely used as a TAC-sparing agent in China that could significantly elevate TAC exposure. However, insufficient data support the dose recommendation of TAC when co-administered with Wuzhi. A total of 305 adult renal transplant patients with 2,541 TAC trough concentrations (C0) were enrolled for population pharmacokinetic (PPK) modeling. CYP3A5 polymorphism was genotyped, and corresponding clinical factors were recorded. Nonlinear mixed-effects modeling and Monte Carlo simulation were used for dose recommendation. PK parameters were calculated based on one-compartment model with first-order absorption and elimination. The estimated total clearance (CL/F) and volume of distribution (Vd/F) of TAC were 23.84 L/h and 1,075.96 L, respectively. Wuzhi, CYP3A5 genotype, hematocrit (HCT), and weight were found to have a significant influence on CL/F. CL/F was significantly lower in the individuals who were CYP3A5 non-expressers and received TAC together with Wuzhi. CYP3A5 genotype (expressers or non-expressers), body weight (40-80 kg), and hematocrit (20 - 40%) were selected as the specific clinical scenarios, and the starting dose of TAC ranged from 1.5 to 4.5 mg when co-administered with Wuzhi. We establish a TAC PPK model comprising Wuzhi as a covariate in renal transplant recipients and recommend an initial dose of TAC when co-administered with Wuzhi, which could provide reference for the individualized regimens of TAC.