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Investigation of sarizotan’s impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

The 5HT1A 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.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacokinetics, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany

    Sonja Krösser, Roland Neugebauer & Andreas Kovar

  2. Department of Non-clinical Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany

    Hugues Dolgos & Markus Fluck

  3. PAREXEL International GmbH, Institute of Clinical Pharmacology, Berlin, Germany

    Karl-Ludwig Rost

Authors
  1. Sonja Krösser
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  2. Roland Neugebauer
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  3. Hugues Dolgos
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  4. Markus Fluck
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  5. Karl-Ludwig Rost
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  6. Andreas Kovar
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Corresponding author

Correspondence to Sonja Krösser.

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Krösser, S., Neugebauer, R., Dolgos, H. et al. Investigation of sarizotan’s impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial. Eur J Clin Pharmacol 62, 277–284 (2006). https://doi.org/10.1007/s00228-006-0101-7

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  • DOI: https://doi.org/10.1007/s00228-006-0101-7

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