Prediction of tacrolimus and Wuzhi tablet pharmacokinetic interaction magnitude in renal transplant recipients.

Abstract

Wuzhi tablets are a dose-sparing agent for tacrolimus (TAC) in China and increase the bioavailability of TAC. The current study aimed to evaluate the pharmacokinetic interaction magnitude of Wuzhi and TAC and explore the potential determinants of this interaction. This study performed a retrospective, self-controlled study of 138 renal transplant recipients who were co-administered TAC and Wuzhi. The trough concentration (C0) of TAC at baseline and 3, 7, 14 and 21 days after Wuzhi co-therapy initiation was measured, and the CYP3A5 polymorphism was genotyped. The corresponding clinical factors were recorded. The ratio of dose-adjusted C0 (C0/D) post- and pre-combination therapy (ΔC0/D) indicates the interaction magnitude. Univariate and multivariate analyses were used to identify determinants and establish the prediction model. ΔC0/D reached a steady state within 14 days. The geometrical mean ΔC0/D was 2.91 (range 1.02-9.49, IQR 2.13-3.80). ΔC0/D was blunted in CYP3A5 expressers (estimated effect: -39.8%, P=.001) and affected by hematocrit (Hct) (+24.0% per 10% increase, P=.005) and baseline C0/D (-31.9% per 1ng·ml-1 ·mg-1 increase, P<.001). The prediction model was ΔC0/D=.319baseline C0/D × 1.398CYP3A5 (expressers=0/non-expressers=1) × 1.024Hct × 1.744, and it explained 28.1% of the variability. Our study is the first attempt to date to give an assessment of the magnitude of pharmacokinetic interaction between TAC and Wuzhi in a cohort of renal transplant recipients, and CYP3A5 genotypes, baseline C0/D and Hct were identified as determinants of this interaction.