Pharmacokinetics of acipimox and of its N-deoxy metabolite following single and repeated oral administration of a sustained release formulation to healthy volunteers

Abstract Acipimox is a lipid lowering agent currently used for the treatment of hyperlipoproteinemia at a dose of 250 mg thrice daily. A sustained release (SR) formulation, containing 500 mg acipimox, has been developed with the aim of reducing the number of daily doses. We report here the pharmacokinetics of acipimox and its N -deoxy metabolite following single and repeated administrations of this new formulation to ten healthy volunteers. Three treatments - single-dose, once-daily administration for 1 week, and twice-daily for a second week - were evaluated over a continuous administration period, and plasma levels were monitored by HPLC following the last dose of each treatment. The pharmacokinetics of acipimox were found to be similar after single and repeated administration of the SR formulation. All three treatments gave maximum plasma levels (mean C max range 4.2–5.1 μg/ml) comparable to the currently used treatment, but with retarded maxima (mean t max 5–6 h). A limited accumulation was detectable following twice-daily administration (mean R A approx. 1.25), and some minor alterations in this plasma profile probably reflected diurnal variations in pharmacokinetic parameters. This regimen maintained, over the 12 h dosing interval, average and minimum steady state concentrations which compare favourably with 8 h dosing of the standard formulation. Plasma levels of the metabolite increased noticeably with repeated dosing and plasma profiles were more variable than for acipimox. However, maximum concentrations (mean C max 0.5–0.8 μg/ml; mean t max 5–11 h) remained consistently lower than unchanged drug, and average steady state concentrations over a dosing interval were about 5-fold lower.