Background Nebivolol (N) has been shown through a number of studies to be a cardioselective β1‐antagonist with vascular endothelial nitric oxide releasing capabilities that exhibits CYP2D6‐mediated polymorphic metabolism. Losartan (L), an ARB, is extensively metabolized by CYP2C9 (a known polymorphic enzyme) and is likely to be used concomitantly. This study examined if co‐administration of N and L alters the pharmacokinetic (PK) characteristics of either agent, or the active metabolite of L, EXP‐3174. Methods This open‐label study was conducted in 24 subjects, genotyped for CYP2D6 status (EM n=20; PM n=4). Using a two‐sequence, two‐treatment design, single doses of 10 mg N (Day 1 or 29), 50 mg L (Day 1 or 29), or their combination (Day 15) were given. Blood samples for PK assessment were taken on Days 1, 15 and 29. Results (see Table) Conclusion There were no clinically meaningful changes observed in the PK of either L or N, confirming that the two agents should be capable of being safely co‐administered. Clinical Pharmacology & Therapeutics (2005) 77, P82–P82; doi: Cmax AUC0‐∞ Parameter Ratio 90% CI Ratio 90% CI EM‐N0.800.68–0.930.890.82–0.97PM‐N0.930.76–1.140.940.68–1.29L0.890.77–1.020.860.81–0.92EXP‐31740.940.86–1.030.980.94–1.02
AIMSIn vitro study showed that benidipine is exclusively metabolized by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of benidipine. METHODSBenidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)-(S)-(+)-α and (R)-(R)-(À)-α isomers of benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam. RESULTSThe exposure of (S)-(S)-(+)-α-benidipine was greater than that of (R)-(R)-(À)-α-benidipine by approximately three-fold following single dose of benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of C max and AUC ∞ for (S)-(S)-(+)-α-benidipine were 0.14 (0.10-0.18) and 0.12 (0.08-0.18), respectively. GMRs (95% CI) of C max and AUC ∞ for (R)-(R)-(À)-α-benidipine were 0.10 (0.06-0.17) and 0.10 (0.06-0.17), respectively. Oral clearances of both isomers were increased equally by approximately 10-fold. There were no significant differences in cardiovascular effect following benidipine administration between control and rifampin treatment. CYP3A activity using midazolam did not appear to correlate with oral clearance of benidipine. CONCLUSIONSAfter single administration of racemic benidipine, enantioselective disposition of (S)-(S)-(+)-αand (R)-(R)-(À)-α-benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure-lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of benidipine should be assessed in hypertensive patients. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 737-745 737• Benidipine is a racemic mixture of two isomers ((R)-(R)-(À)-α and (S)-(S)-(+)-α).• Our previous study indicated that benidipine was metabolized by CYP3A4 and CYP3A5.• Rifampin is a potent inducer of CYP3A4 that can decrease the antihypertensive effects of calcium channel blockers. WHAT THIS STUDY ADDS• A clinical study in healthy subjects was conducted to evaluate the enantioselective disposition of benidipine.• This study describes for the first time the effect of rifampin on the pharmacokinetic and pharmacodynamic properties of benidipine and its enantiomers to establish the mechanism of the drug interaction. Study design flow chart Effect of rifampin on benidipine PK/PD Br J Clin Pharmacol (2019) 85 737-745 739 Effect of rifampin on benidipine PK/PD Br J Clin Pharmacol (2019) 85 737-745 745
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