Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.
Article Details
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Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M
Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.
J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7.
- PubMed ID
- 28881378 [ View in PubMed]
- Abstract
Istradefylline, a selective adenosine A2A inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric mean ratio of log-transformed data, rifampin reduced istradefylline exposure: Cmax , 0.55 (90%CI, 0.49-0.62); AUClast , 0.21 (90%CI, 0.19-0.22); and AUCinf , 0.19 (90%CI, 0.18-0.20), indicating nonequivalence. These changes were primarily because of the effect of rifampin on the elimination parameters of istradefylline; mean CL/F was increased from 4.0 to 20.6 L/h, and mean t1/2 was reduced from 94.8 to 31.5 hours. The effect of rifampin coadministration on the disposition of the istradefylline M1 and M8 metabolites was inconsistent and variable. Furthermore, as exposure of the istradefylline M1 and M8 metabolites in plasma was generally <9% of total drug exposure, it would be expected to have a negligible impact on the pharmacodynamic effect of istradefylline. Caution should be exercised when istradefylline is administered concurrently with strong CYP3A4 inducers and dose adjustment considered.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Istradefylline Adenosine receptor A2a Protein Humans YesAntagonistDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Istradefylline Cytochrome P450 1A1 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 2B6 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 2C18 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Istradefylline Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareIstradefyllineKetoconazole The serum concentration of Istradefylline can be increased when it is combined with Ketoconazole.
