Investigation of sarizotan's impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial.
OBJECTIVE
The 5HT(1A) receptor agonist sarizotan is in clinical development for the treatment of dyskinesia, a potentially disabling complication in Parkinson's disease. We investigated the effect of sarizotan on the clinical pharmacokinetics of probe drugs for cytochrome P450 (CYP) to evaluate the risk of CYP-related drug-drug interactions.


METHODS
This was a double-blind, randomised, two-period cross-over interaction study with repeated administration of 5 mg sarizotan HCl or placebo b.i.d. for 8 days in 18 healthy volunteers. On day 4, a single dose of 100 mg metoprolol (CYP2D6 probe) was administered. On day 8, single doses of 100 mg caffeine (CYP1A2 probe), 50 mg diclofenac (CYP2C9 probe), 100 mg mephenytoin (CYP2C19 probe) and 7.5 mg midazolam (CYP3A4 probe) were simultaneously applied. Pharmacokinetic parameters for probe drugs and their metabolites in plasma and urinary recovery were determined.


RESULTS
Concentration-time profiles and pharmacokinetic parameters of all probes and their metabolites remained unchanged after co-administration of sarizotan, compared with placebo. Analysis of variance of the area under the plasma concentration-time curve for probe drugs/metabolites, metabolic ratios and urinary excretion resulted in 90% confidence intervals within the acceptance range (0.8-1.25), indicating the absence of drug-drug interactions.


CONCLUSIONS
At a dose higher than that intended for clinical use (1 mg b.i.d.), sarizotan had no effect on the metabolism and pharmacokinetics of specific probe drugs for CYP isoenzymes 1A2, 2C19, 2C9, 2D6 and 3A4. Pharmacokinetic interactions with co-administered drugs metabolised by these CYP isoforms are not expected, and dose adjustment of co-administered CYP substrates is not necessary.
Krösser
Sonja
S
Clinical Pharmacology and Pharmacokinetics, Merck KGaA, Darmstadt, Germany. Sonja.Kroesser@merck.de
Neugebauer
Roland
R
Dolgos
Hugues
H
Fluck
Markus
M
Rost
Karl-Ludwig
KL
Kovar
Andreas
A
D000293:Adolescent; D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000032:analysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D006899:Mixed Function Oxygenases / Q000032:analysis; D015335:Molecular Probes / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology; D010599:Pharmacokinetics
D000978:Antiparkinson Agents; D007527:Isoenzymes; D015335:Molecular Probes; D009930:Organic Chemicals; C443959:sarizotan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human