12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson’s disease is unknown. In in vitro studies and in in vivo animal studies, istradefylline was demonstrated to be an adenosine A2A receptor antagonist.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of NOURIANZ (40 mg or 160 mg [4 times the maximum recommended dosage] once daily for 14 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacin-controlled, multiple-dose, blinded, parallel group study. There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations of istradefylline.

12.3 Pharmacokinetics

Istradefylline exhibits dose-proportional pharmacokinetics after multiple oral doses from 20 mg to 80 mg (2 times the maximum recommended dosage). Steady-state was reached within 2 weeks of once-daily dosing. The pharmacokinetics of istradefylline were similar in PD patients and healthy subjects.

Absorption

The median time to reach the maximum concentration (Tmax) for istradefylline was about 4 hours under fasted dosing conditions.

Effect of Food

Istradefylline exposure, represented by the area under the curve over time to infinity (AUCinf), increased 1.25-fold when NOURIANZ was coadministered with a standard high-fat meal, compared with administration in a fasted state. Istradefylline maximum plasma concentrations (Cmax) increased by 1.64-fold and Tmax was shortened by 1 hour when NOURIANZ was administered with a high-fat meal. These differences in pharmacokinetic parameters are not expected to be clinically significant [see Dosage and Administration (2.1)].

Distribution

The plasma protein binding of istradefylline was approximately 98%. The apparent volume of distribution (Vd/F) of istradefylline is approximately 557 liters.

Elimination

The total clearance of istradefylline is approximately 4.6 L/hour. The mean terminal half-life (t1/2) for istradefylline at steady-state is approximately 83 hours.

Metabolism

In humans, istradefylline is exclusively eliminated via metabolism. In vitro studies indicate that istradefylline is primarily metabolized via CYP1A1 and CYP3A4, with minor contribution from CYP1A2, 2B6, 2C8, CYP2C9, CYP2C18, and 2D6. Six metabolites have been identified in human plasma. These metabolites each account for less than 10% of the exposure of the parent drug.

Excretion

Approximately 48% of a 40-mg oral dose of 14C-istradefylline was eliminated in feces, and 39% in urine. Unchanged istradefylline was not detected in urine.

Specific Populations

In patients with moderate hepatic impairment (Child-Pugh Class B), the steady-state exposure (AUC0-24) of istradefylline is predicted to be 3.3-fold higher relative to healthy subjects, based on the estimated mean terminal half-life [see Use in Specific Populations (8.7)]. Based on population pharmacokinetic analyses, no clinically relevant changes in the pharmacokinetics of istradefylline were observed based on age, sex, weight, or race. No clinically relevant changes in istradefylline exposure were observed in patients with severe renal impairment (CrCL 15-29 mL/min) or mild hepatic impairment. NOURIANZ has not been studied in patients with ESRD (CrCL < 15 mL/min), ESRD patients requiring hemodialysis, or severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6, 8.7)].

Steady-state systemic exposure to istradefylline (40 mg) is 38% to 54% lower in tobacco smokers (who smoke 20 or more cigarettes per day) when compared with non-smokers matched for age, gender, and body weight [see Specific Populations (8.8)].

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

Drug-Metabolizing Enzyme Inhibition

Istradefylline is a weak inhibitor of CYP3A4, but not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, or 2D6 in vitro.

Drug-Metabolizing Enzyme Induction

Istradefylline was a weak inducer of CYP3A4 but not an inducer of CYP1A2 and 2B6 when tested in vitro. However, clinical drug-drug interaction studies with a CYP3A4 substrate (i.e., midazolam) showed no induction of CYP3A4.

Transporters

Istradefylline was not a substrate for drug transporters P-gp, BCRP, OATP1B1, or OATP1B3 when tested in vitro. Istradefylline was a weak inhibitor for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K, but not an inhibitor of OAT3 when tested in vitro.

In Vivo Assessment of Drug Interactions

Effect of Other Drugs on Istradefylline

Strong CYP3A4 Inhibitors

Coadministration of ketoconazole (200 mg twice daily for 4 days) with a single dose of istradefylline (40 mg) increased the AUCinf of istradefylline by 2.5-fold, but had no effect on Cmax [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

Coadministration of rifampin (600 mg daily for 20 days) with a single dose of istradefylline (40 mg) reduced the Cmax and AUCinf of istradefylline by 45% and 81% respectively, when compared with istradefylline administered alone [see Drug Interactions (7.1)].

Effect of Istradefylline on Other Drugs

CYP3A4 Substrates

Coadministration of istradefylline at higher than the recommended doses (80 mg for 14 days) with a single dose of midazolam (10 mg) increased midazolam AUCinf 2.4-fold, and Cmax by 1.6-fold, when compared with midazolam administered alone. Coadministration of lower doses of istradefylline (5 mg and 20 mg) with midazolam (7.5 mg) did not have these effects [see Drug Interactions (7.2)].

Coadministration of istradefylline (40 mg daily for 17 days) with a single dose of atorvastatin (40 mg) increased the Cmax and AUCinf of atorvastatin by 1.5-fold, compared with atorvastatin alone [see Drug Interactions (7.2)].

P-glycoprotein Substrates

Coadministration of istradefylline (40 mg daily for 21 days) with a single dose of digoxin (0.4 mg) increased the Cmax and AUCinf of digoxin by 33% and 21%, respectively, when compared with digoxin alone [see Drug Interactions (7.2)].

Carbidopa/Levodopa

Coadministration of istradefylline (80 mg [two times the recommended maximum dosage] daily for 14 days) with a single dose of carbidopa/levodopa (50/200 mg) did not affect the pharmacokinetics of carbidopa/levodopa. Also, coadministration of istradefylline (20 mg or 40 mg daily for 14 days) with carbidopa/levodopa (25/100 mg three times a day for 14 days) did not affect the systemic exposure of carbidopa/levodopa.