Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with Parkinson's disease.
This model-based analysis quantifies the population pharmacokinetics (PK) of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy subjects and patients with Parkinson's disease, including the estimation of covariate effects on istradefylline PK parameters. Istradefylline plasma concentration data from 8 phase 1 and 8 phase 2/3 studies conducted in 1449 patients and normal, healthy volunteers aged from 18 to 87 years were best described by a 2-compartment model with first-order absorption parameterized in terms of apparent oral clearance (CL/F), apparent central volume of distribution (V2/F), apparent intercompartmental clearance (Q/F), apparent peripheral volume of distribution (V3/F) and a first-order absorption rate-constant (Ka). The typical population PK parameters were CL/F (5.76 L/h), V2/F (198 L), Q (21.6 L/h), V3/F (307 L), and Ka (0.464 h(-1)) for a 70-kg, nonsmoking Caucasian who had 55.6 kg of lean body mass, no presence of CYP3A4 inhibitors, and unknown food status. Smoking and CYP3A4 inhibitors as concomitant medications were important predictors of istradefylline exposure. Istradefylline area under the concentration-time curve at steady-state increased 35% (95% confidence interval, 18%-55%) in the presence of CYP3A4 inhibitors and decreased 38% (95% confidence interval, 26%-50%) in smokers. The population PK model described the observed concentration data well and was deemed appropriate for further evaluation of the istradefylline exposure-response relationship in patients with Parkinson's disease.
Knebel
William
W
Metrum Research Group LLC, Tariffville, Connecticut, USA. billk@metrumrg.com
Rao
Niranjan
N
Uchimura
Tatsuo
T
Mori
Akihisa
A
Fisher
Jeannine
J
Gastonguay
Marc R
MR
Chaikin
Philip
P
D058917:Adenosine A2 Receptor Antagonists / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D016022:Case-Control Studies; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D016208:Databases, Factual; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010300:Parkinson Disease / Q000188:drug therapy*; D011687:Purines / Q000493:pharmacokinetics*; D012907:Smoking / Q000009:adverse effects; D014018:Tissue Distribution; D055815:Young Adult
D058917:Adenosine A2 Receptor Antagonists; D065692:Cytochrome P-450 CYP3A Inhibitors; D011687:Purines; C111599:istradefylline; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human