Effect of CYP3A5 polymorphisms on pharmacokinetic interaction between cyclosporine and diltiazem in Thai renal allograft recipients

Abstract

Cyclosporine (CsA) is frequently coadministration with Diltiazem (DTZ) because the latter has possible beneficial effect on the economic impact associated with reduction of the daily dose of CsA. The interaction between CsA and DTZ results in increased CsA blood concentration due to the CYP3A5 inhibitory effect of DTZ. Studies about the effect of CYP3A5 polymorphism on CsA pharmacokinetics when comedication with DTZ have not been clearly defined. In Thailand there has never been study about the effect of CYP3A5 polymorphism on CsA blood level at 2 hour post dose (C₂) either in patient using CsA alone or concurrently use with DTZ. The purpose of this study was to compare the effect of DTZ on CsA level-to-dose ratio (dose-adjusted C₂) in patients with different CYP3A5 genotype. The outcome was to determine the difference in CsA C₂ before and after coadministration with DTZ 30mg/day for 1 month (without any change in CsA dosage regimen). The results indicated that dose-adjusted C₂ showed the trend increased in CYP3A5*1/*1 patients (N=5) even though this increment was not reaching the statistically significant level which might due to the small sample size (188.10±87.93 vs 217.88±58.67 ng/ml per mg/kg/day, p= 0.107). In contrast, dose-adjusted C₂ in CYP3A5*1/*3 and CYP3A5*3/*3 patients were less affected, dose-adjusted C₂ before and after DTZ used were 349.63±158.36 vs 304.12±105.89 ng/ml per mg/kg/day respectively, p=0.367 in CYP3A5*1/*3 patients (N=13) while in CYP3A5*3/*3 patients (N=20) dose-adjusted C₂ before and after DTZ used were 298.91±131.37 vs 316.61±120.73 ng/ml per mg/kg/day, p=0.535. In conclusion, the effect of DTZ as CsA-sparing agent show more prominent effect in patients carrying CYP3A5*1/*1 as compared to the others; the dose-adjusted C₂ were higher when the drug was concurrently used even with low dose of DTZ (30mg/day). CsA level must be closely monitored and CsA daily dose should be adjusted accordingly to prevent toxicity of CsA overdose, especially when DTZ is coadministered in a higher dosage.