PHARMACOKINETICS AND DOSE PROPORTIONALITY OF D2-AGONIST MK-458 (HPMC) IN PARKINSONISM

To investigate the pharmacokinetic profile, bioavailability, and dose proportionality of the D2-agonist MK-458 (hydroxypropylmethylcellulose tablet, a sustained release formulation), a 4-period crossover study was conducted in 10 patients with mild to moderate Parkinson's disease (mean age = 63y; 1 woman, 9 men). Following a titration phase to induce tolerance, each patient was given single oral doses of 6, 12 and 18mg and a single intravenous 40-mu-g dose (5-mu-g/h over 8h). The maximum concentrations of MK-458 observed in plasma after oral administration were 139, 240 and 344 ng/L for the 6, 12 and 18mg doses, respectively, and occurred after 8.0, 9.0 and 5.5h, respectively. Mean areas under the plasma concentration-time curves were 1728, 2849 and 5484 ng/L . h, respectively. The mean plasma half-life was 3.8h and mean plasma clearance was 3390 ml/min (203.4 L/h). The bioavailability (almost-equal-to 5%) was very similar for the 3 tablet formulations tested. The disposition of MK-458 was independent of the dose over the range of doses studied.