BIOEQUIVALENCE OF 2 TABLET FORMULATIONS OF NADOLOL USING SINGLE AND MULTIPLE-DOSE DATA - ASSESSMENT USING STEREOSPECIFIC AND NONSTEREOSPECIFIC ASSAYS

Nadolol, a nonspecific beta-blocker, is a racemate composed of equal a mounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, an d SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequi valence of two formulations of nadolol were assessed in 20 healthy mal e subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compre ssed tablet formulations, each containing 80 mg of nadolol, with diffe rent in vitro dissolution profiles that met current USP requirements w ere used. The four treatments were single and multiple doses of granul ated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses o f nadolol were administered after an overnight fast. Serial blood samp les were collected up to 72 h following the single dose and during mul tiple dose treatments, following day 6 and 7 doses. Validated highperf ormance 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 C-ma x, and AUC values were significantly greater for SQ-12150 when compare d to other nadolol stereoisomers obtained after a single dose or at st eady state. However, T-max and T-1/2 values were similar among the fou r isomers. The observed steady state AUC(tau) values for nadolol (2278 -2331 ng h/mL) or its stereoisomers (550-874 ng h/mL) were significant ly greater than those predicted from the single dose AUC(inf) values ( nadolol, 1840-1845 ng h/mL; isomers, 450-713 ng h/mL). The intrasubjec t variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two for mulations were bioequivalent for nadolol (C-max = 0.98 [84%, 117%]; AU C(inf) = 1.03 [93%, 116%]) and SQ-12150 (C-max = 1.12 [89%, 122%]; AUC (inf) = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C -max = 1.07 [84%, 118%]; AUC(inf) = 1.02 [91%, 113%]) at steady state.