UNLABELLED: INTRODUCTION AND OBJECTIVE: Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. MATERIALS AND METHODS: The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS: A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS: In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.

Center for Innovative Drug Development and Therapeutic Trials for Africa College of Health Sciences Addis Ababa University Addis Ababa Ethiopia

Department of Anthropology and Human Genetics Faculty of Science Charles University Prague Czech Republic

Department of Family Medicine Sultan Qaboos University Hospital Muscat Sultanate of Oman

Department of Genetics and Evolution Anthropology Unit University of Geneva 30 Quai Ernest Ansermet 1205 Geneva Switzerland

Department of Genetics College of Medicine and Health Sciences Muscat Sultanate of Oman

Department of Genetics Sultan Qaboos University Hospital Muscat Sultanate of Oman

Department of Medical Genetics 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Pharmacology and Clinical Pharmacy College of Health Sciences Addis Ababa University Addis Ababa Ethiopia

Department of Pharmacology and Clinical Pharmacy Sultan Qaboos University Muscat Sultanate of Oman

Division of Clinical Pharmacology and Toxicology Geneva University Hospitals and University of Geneva Rue Gabrielle Perret Gentil 4 1211 Geneva Switzerland

Global One Health Initiative Office of International Affairs The Ohio State University Columbus OH USA

Institute of Genetics and Genomics of Geneva Geneva Switzerland

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University Prague Czech Republic

Oman Specialty Board Muscat Sultanate of Oman

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Joint Analysis of Phenotypic and Genomic Diversity Sheds Light on the Evolution of Xenobiotic Metabolism in Humans

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NCT02789527