Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6ß-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.

WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6ß-hydroxycortisol (6ß-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6ß-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6ß-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6ß-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6ß-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6ß-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6ß-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.

Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib.

This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C(max)) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).