A study of the pharmacokinetic interaction of istradefylline, a novel therapeutic for Parkinson's disease, and atorvastatin.
The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n=16) or placebo (n=4) daily for 14 days. Plasma samples collected for 96 hours after atorvastatin administration, alone and in combination, were analyzed for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin. Istradefylline increased atorvastatin C(max) (53%), AUC(0-infinity) (54%), and t((1/2)) (27%); and increased AUC(0-infinity) for orthohydroxy atorvastatin (18%), but had no significant effect on its C(max) or t((1/2)); and had minimal effect on parahydroxy atorvastatin AUC(0-infinity). The lack of inhibition by istradefylline on metabolite systemic exposure, combined with increased atorvastatin systemic exposure, suggests a predominant P-glycoprotein inhibitory effect of istradefylline.
Kyowa Pharmaceutical Inc, 212 Carnegie Center, Suite 101, Princeton, NJ 08540, USA. rao.niranjan@kyowa-kpi.com
N
N
Rao
B
B
Dvorchik
N
N
Sussman
H
H
Wang
K
K
Yamamoto
A
A
Mori
T
T
Uchimura
P
P
Chaikin
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000069059:Atorvastatin / Q000031:analogs & derivatives; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
C518963:2-hydroxyatorvastatin; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000978:Antiparkinson Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011687:Purines; D011758:Pyrroles; C111599:istradefylline; D003577:Cytochrome P-450 Enzyme System; C518964:4-hydroxyatorvastatin; D000069059:Atorvastatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A