Verification of a cocktail approach for quantitative drug–drug interaction assessment: a comparative analysis between the results of a single drug and a cocktail drug

Abstract

1. A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use as a quantitative drug-drug interactions (DDIs) assessment was evaluated.

2. We administered a cocktail drug (caffeine, losartan, omeprazole, dextromethorphan, midazolam) with rifampicin, cimetidine or fluvoxamine. A comparative analysis was performed between the results of a cocktail study and single studies. The results of single studies were obtained from a literature review and the trials of single substrate separate administration.

3. A strong positive correlation of the AUC ratio of all drugs between single studies and the cocktail study was obtained. The ratio of AUC change of 12 combinations converged to 0.82–1.09, and 2 combinations ranged between 0.74–1.32.

4. The differences in the degree of interaction between the single studies and cocktail study are acceptable to evaluate DDIs for almost all combinations. Our results indicate that a cocktail study is an adequate and quantitative evaluation method for DDIs.

Keywords:

• Cocktail approach
• cytochrome P450
• drug–drug interaction
• verification
• literature review
• comparative analysis
• inducer
• inhibitor

Author contribution statement

M.M., S.U., K.O., N.I., J.K., H.W, and N.N. were involved in the conception and trial design. C.K, A.H, N.K., K.O., N.I., and H.W were responsible for patient care and clinical specimen collection. M.M., S.U., and S.T. performed data analysis, interpretation, and statistical analysis. M.M. and S.U. wrote the manuscript with input from all authors.

Ethical approval

All studies were approved by the Ethics Committee of Hamamatsu University School of Medicine, Japan, and all participants provided written informed consent prior to participation in the study. These studies were conducted in full compliance with the principles of the Helsinki Declaration.

Clinical trial registration

The cocktail study and single administration study were registered at the UMIN Clinical Trials Registry (UMIN000016113 and 000020286).

UMIN000016113: Influence of cytochrome P450 phenotypes on changes of drug-induced these enzyme activities.

UMIN000020286: Evaluation of drug interactions of cytochrome P450 by single-substrate administrations and the cocktail method.

Acknowledgements

The authors thank T. Sasano, M. Ozawa, M. Shinohara, and Y. Nogami for their valuable advice and technical support. This study was supported by JSPS KAKENHI Grant number JP 26460202. We thank Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This work was supported by JSPS KAKENHI grant number JP 26460202.