Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective.
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.
School of Pharmaceutical Sciences, Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, PR China.
J-L
JL
Li
X-D
XD
Wang
S-Y
SY
Chen
L-S
LS
Liu
Q
Q
Fu
X
X
Chen
L-C
LC
Teng
C-X
CX
Wang
M
M
Huang
D000293:Adolescent; D000328:Adult; D000465:Algorithms; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D016009:Chi-Square Distribution; D002681:China; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004110:Diltiazem / Q000008:administration & dosage*; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000276:immunology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D011446:Prospective Studies; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D016559:Tacrolimus