Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins.
- Rollason V Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, Switzerland. Victoria.Rollason@hcuge.ch.
- Mouterde M Department of Genetics and Evolution (GENEV), Anthropology Unit, University of Geneva, 30, Quai Ernest-Ansermet, 1205 Geneva, Switzerland. Mederic.Mouterde@unige.ch.
- Daali Y Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, Switzerland.
- Čížková M Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech Republic.
- Priehodová E Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech Republic.
- Kulichová I Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech Republic.
- Posová H Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Petanová J Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Mulugeta A Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
- Makonnen E Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
- Al-Habsi A Oman Specialty Board, Muscat, Sultanate of Oman.
- Davidson R Department of Family Medicine, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.
- Al-Balushi KK Department of Pharmacology and Clinical Pharmacy, Sultan Qaboos University, Muscat, Sultanate of Oman.
- Al-Thihli K Department of Genetics, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.
- Cerná M Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
- Al-Yahyaee S Department of Genetics, College of Medicine and Health Sciences, Muscat, Sultanate of Oman.
- Černý V Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech Republic.
- Yimer G Global One Health Initiative, Office of International Affairs, The Ohio State University, Columbus, OH, USA.
- Poloni ES Department of Genetics and Evolution (GENEV), Anthropology Unit, University of Geneva, 30, Quai Ernest-Ansermet, 1205 Geneva, Switzerland.
- Desmeules J Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, Switzerland.
- 2020-08-28
Published in:
- Drug safety. - 2020
English
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.
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.
- Language
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- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1007/s40264-020-00983-8
- PMID 32851583
- Persistent URL
- https://sonar.ch/global/documents/229850
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