title: Population pharmacokinetic-pharmacodynamic analysis of istradefylline in patients with Parkinson disease.
abstract: This model-based analysis quantifies the population pharmacokinetic-pharmacodynamic efficacy and safety/tolerability relationships of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy participants and patients with Parkinson disease. Data from 6 phase 2/3 clinical trials comprised the population database, with 1760 and 1798 patients contributing to the efficacy and safety/tolerability analyses, respectively. The relationship between istradefylline area under the curve at steady state and percentage OFF time was described by a nonlinear model (Emax) based on time for the disease progression/placebo response component and an Emax model for the effect of istradefylline. The typical maximum decrease in percentage OFF time due to istradefylline exposure would be 5.79% (95% confidence interval = 4.09%-7.49%) with one-half of the maximum effect reached at an exposure of 1690 ng × hr/mL (95% confidence interval = 199-3180 ng × hr/mL). The pharmacokinetic-pharmacodynamic relationships for dyskinesia and dizziness were described by an Emax model, and for nausea, a power model was used. The probabilities of dyskinesia and dizziness are expected to plateau at a dose of 40 mg/d, and the probability of nausea is expected to continually rise as the dose is increased. Collectively, these results support a starting istradefylline dose of 20 to 40 mg/d.
authors.affiliation: Metrum Research Group LLC, Tariffville, CT, USA.
authors.forename: William
authors.initials: W
authors.lastname: Knebel
authors.forename: Niranjan
authors.initials: N
authors.lastname: Rao
authors.forename: T
authors.initials: T
authors.lastname: Uchimura
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mori
authors.forename: Jeannine
authors.initials: J
authors.lastname: Fisher
authors.forename: Marc R
authors.initials: MR
authors.lastname: Gastonguay
authors.forename: Philip
authors.initials: P
authors.lastname: Chaikin
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D020820:Dyskinesias / Q000209:etiology; D006801:Humans; D008954:Models, Biological; D009325:Nausea / Q000139:chemically induced; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; C111599:istradefylline