Bioequivalence of Two Tablet Formulations of Nadolol Using Single and Multiple Dose Data: Assessment Using Stereospecific and Nonstereospecific Assays

Abstract

Nadolol, a nonspecific β-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both Cmax and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, Tmax and T1/2 values were similar among the four isomers. The observed steady state AUCτ values for nadolol (2278-2331ng h/mL) or its stereoisomers (550-874ng h/mL) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845ng h/mL; isomers, 450-713ng h/mL). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (Cmax= 0.98 [84%, 117%]; AUCinf= 103 [93%, 116%]) and SQ-12150 (Cmax= 1.12 [89%, 122%]; AUCinf= 0.98 [82%, 119%]) after a single dose, and only for nadolol (Cmax= 107 [84%, 118%]; AUCinf= 102 [91%, 113%]) at steady state.