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 = 63 y; 1 woman, 9 men). Following a titration phase to induce tolerance, each patient was given single oral doses of 6, 12 and 18 mg and a single intravenous 40 micrograms dose (5 micrograms/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 18 mg doses, respectively, and occurred after 8.0, 9.0 and 5.5 h, respectively. Mean areas under the plasma concentration-time curves were 1728, 2849 and 5484 ng/L.h, respectively. The mean plasma half-life was 3.8 h and mean plasma clearance was 3390 ml/min (203.4 L/h). The bioavailability (approximately 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.
Cutler
N R
NR
California Clinical Trials, Beverly Hills, California.
Reines
S A
SA
McLean
L F
LF
Sramek
J J
JJ
Porras
A G
AG
Hand
E L
EL
D000284:Administration, Oral; D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D015259:Dopamine Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007785:Lactose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008747:Methylcellulose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D010078:Oxazines; D010300:Parkinson Disease / Q000097:blood / Q000378:metabolism*; D013607:Tablets
D000978:Antiparkinson Agents; D003692:Delayed-Action Preparations; D015259:Dopamine Agents; D010078:Oxazines; D013607:Tablets; D008747:Methylcellulose; C071191:MK 458; D007785:Lactose