PHARMACOKINETICS OF ACIPIMOX AND OF ITS N-DEOXY METABOLITE FOLLOWING SINGLE AND REPEATED ORAL-ADMINISTRATION OF A SUSTAINED-RELEASE FORMULATION TO HEALTHY-VOLUNTEERS

Acipimox is a lipid lowering agent currently used for the treatment of hyperlipoproteinemia at a dose of 250 mg thrice daily. A sustained re lease (SR) formulation, containing 500 mg acipimox, has been developed with the aim of reducing the number of daily doses. We report here th e pharmacokinetics of acipimox and its N-deoxy metabolite following si ngle and repeated administrations of this new formulation to ten healt hy volunteers. Three treatments - single-dose, once-daily administrati on 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 pharmacokinetic s of acipimox were found to be similar after single and repeated admin istrations of the SR formulation. All three treatments gave maximum pl asma levels (mean C(max) range 4.2-5.1 mug/ml) comparable to the curre ntly used treatment, but with retarded maxima (mean t(max) 5-6 h). A l imited accumulation was detectable following twice-daily administratio n (mean R(A) approx. 1.25), and some minor alterations in this plasma profile probably reflected diurnal variations in pharmacokinetic param eters. 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 metaboli te increased noticeably with repeated dosing and plasma profiles were more variable than for acipimox. However, maximum concentrations (mean C(max) 0.5-0.8 mug/ml; mean t(max) 5-11 h) remained consistently lowe r than unchanged drug, and average steady state concentrations over a dosing interval were about 5-fold lower.