Pharmacokinetic disposition of nebivolol in extensive and poor CYP2D6 metabolizers

Abstract

Background Nebivolol (N) is considered to be a unique cardiovascular agent studied worldwide for the treatment of hypertension, CHF and other cardiovascular conditions owing to vascular endothelial nitric oxide stimulating capabilities and its highly selective β1-antagonism. It is directly glucuronidated to a set of active metabolites believed to make a clinically important contribution to therapy. It is also metabolized by polymorphic CYP2D6 to active hydroxy-moeities, which are further glucuronidated. The present study examined the steady-state kinetics of N in extensive (EM) and poor (PM) CYP2D6 metabolizers. Methods Twenty-two healthy adult subjects completed (16 EMs and 6 PMs). N (10 mg) was administered once daily for 14 days, with steady-state assessments on Days 12 thru 14 and PK profiling on Day 14 for N and nebivolol glucuronides (G-UD). Results N was well tolerated by both groups. (see Table) Conclusions Despite the PK differences between EMs and PMs, clinical trials have established that there are no clinical efficacy or safety differences between the two groups. Clinical Pharmacology & Therapeutics (2005) 77, P77–P77; doi: 10.1016/j.clpt.2004.12.184 Table 1. EM PM Parameter N G-UD N G-UD AUC (ng hr/mL) 19.73 433.2 633.2 2804 Cmax (ng/mL) 3.45 52.76 32.11 220.5 Tmax (hr) 1.19 2.69 3.67 3.67 t1/2 (hr) 12.66 7.43 56.05 32.81 CI/F (L/hr) 657.4 44.31 16.32 3.89