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Population Pharmacokinetic‐Pharmacodynamic Analysis of Istradefylline in Patients With Parkinson Disease
Author(s) -
Knebel William,
Rao Niranjan,
Uchimura T.,
Mori Akihisa,
Fisher Jeannine,
Gastonguay Marc R.,
Chaikin Philip
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011420566
Subject(s) - medicine , tolerability , pharmacodynamics , dyskinesia , pharmacokinetics , placebo , nausea , population , confidence interval , anesthesia , pharmacology , parkinson's disease , adverse effect , disease , alternative medicine , environmental health , pathology
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.