Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective.
Author(s): Li JL, Wang XD, Chen SY, Liu LS, Fu Q, Chen X, Teng LC, Wang CX, Huang M
Affiliation(s): School of Pharmaceutical Sciences, Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, PR China.
Publication date & source: 2011-08, Pharmacogenomics J., 11(4):300-6. Epub 2010 Jun 1.
Publication type: Randomized Controlled Trial; Research Support, Non-U.S. Gov't
The impact of CYP3A5*3, a CYP3A5 nonexpresser genotype, on inhibitory effects of diltiazem on tacrolimus metabolism has not been assessed. In retrospective study, when coadministered with diltiazem, mean increments in dose-adjusted C(0D7), C(max) and AUC(0-12 h) for tacrolimus were larger in CYP3A5 expressers than in CYP3A5 nonexpressers (48.7 vs 3.7%, 31.7 vs 17.2% and 38.2 vs 18.5%, respectively). Subsequently, a prospective study was carried out, patients were randomized to algorithm-predicted dosing or standard dosing. For CYP3A5 expressers, an algorithm guided by CYP3A5 and diltiazem significantly reduced tacrolimus maintenance dosage (P=0.009) and improved the accuracy of tacrolimus initial dose, resulting in reduction in out-of-range C(0) after initial dose (P=0.002) and dose adjustments (P=0.004). However, for CYP3A5 nonexpressers, primary end points were not achieved, and tacrolimus-sparing effect of diltiazem was not remarkable. Our study results show that CYP3A5 genotype-guided tacrolimus-diltiazem combination is a promising therapy in renal transplant recipients in the early postoperative stage.