Effect of bifendate on the pharmacokinetics of cyclosporine in relation to the CYP3A4*18B genotype in healthy subjects

Abstract

Aim:To evaluate the potential drug-drug interactions between bifendate and cyclosporine, a substrate of CYP3A4, in relation to different CYP3A4*18B genotype groups. Methods: Eighteen unrelated healthy subjects (six CYP3A4*1*1, six CYP3A4*1/*18B, and six CYP3A4*18/*18B) were selected for this study. After repeated oral administration of a placebo or bifendate (three times daily for 14 d), the wholeblood level of cyclosporine was measured using high performance liquid chromatography-electrospray mass spectrometry (HPLC/ESI-MS). This study was carried out in a two-phase randomized crossover manner. Results: After the treatment with bifendate, the areas under the curve (AUC 0-24 and AUC 0-∞ ) decreased significantly by 9.7%±3.7% (P=0.01) and 19.2%±16.8% (P=0.001) in CYP3A4*1/*1 subjects, 11.3%±9.4% (P=0.03) and 10.5%±9.6% (P=0.043) in CYP3A4*1/*18B subjects, and 40.2%±14.7% (P=0.02) and 37.5%±15.8% (P=0.003) in CYP3A4*18B/*18B subjects. Meanwhile, the decreases in the AUC 0-24 and AUC 0-∞ values in the three groups were significantly different (using one-way analysis of variance, P=0.001 and P=0.001), and the change in the CYP3A4*18B/*18B group was greater than that in the other two groups. The oral clearance of cyclosporine was altered in all the subjects, with substantial increases by 10.2%±4.4% (P=0.004) in CYP3A4*1/*1 subjects, 14.0%±12.0% (P=0.048) in CYP3A4*1/*18B subjects, and 32.4%±21.7% (P=0.013) in CYP3A4*18B/*18B subjects. Conclusion: These results suggest that bifendate decreases the plasma concentration of cyclosporine in a CYP3A4 genotypedependent manner.

CYP3A4∗18B and CYP3A5∗3 polymorphisms contribute to pharmacokinetic variability of cyclosporine among healthy Chinese subjects

“…Several studies have indicated http://dx.doi.org/10.1016/j.ejps.2015.05.011 0928-0987/Ó 2015 Elsevier B.V. All rights reserved. that this SNP, which occurs with high frequency in Chinese subjects, contributes to the variable PK of cyclosporine in those subjects (Hu et al, 2007;Zeng et al, 2009). Study in renal transplant patients also showed that both trough concentration (C 0 ) and 2 h post-dose concentration (C 2 ) were significantly lower in the CYP3A4⁄18B/⁄18B group than the CYP3A4⁄1/⁄1 (wildtype) group (Qiu et al, 2008).…”

Clinical implementation of pharmacogenetics in kidney transplantation: calcineurin inhibitors in the starting blocks

“…A novel interesting lead is related to the effect of the CYP3A4*18B allele [rs28371759, MAF in the Asian population = 2% (source 1000 Genomes)] in the Asian population . The reported data consistently suggest an increased CsA clearance for healthy Asian individuals carrying this gain of function allele . This effect of the CYP3A4*18B allele on CsA PK has been recently confirmed in Chinese renal transplant recipients but only when considering CsA dose‐adjusted C 2 and not dose‐adjusted C 0 .…”

Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis

“…CYP3A4*18B leads to a G to A substitution at position 82266 (7), and several studies indicate that this SNP is related to the PK of cyclosporin. Hu et al (6) and Zeng et al (16) found that the CYP3A4*18B genotype affected cyclosporin PK in healthy Chinese individuals. Our previous study in 103 Chinese renal transplant patients also showed that both cyclosporin trough concentration (C 0 ) and 2-h post-dose concentration (C 2 ) were significantly lower in the group of CYP3A4*18B ⁄ *18B homozygous mutants compared with those carrying CYP3A4*1 ⁄ *1 (8).…”