title: Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers.
abstract: This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.
authors.affiliation: CEA, LIST, Data Analysis and Systems Intelligence Laboratory, Gif-sur-Yvette, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Lenuzza
authors.affiliation: Clinical Investigation Center (CIC-1425), CHU Bichat Claude Bernard, Paris, France.|INSERM, IAME, UMR1137, University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Duval
authors.affiliation: CEA, DSV, iBiTecS, Pharmacology and Immunoanalysis Unit, Gif-sur-Yvette, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: CEA, LIST, Data Analysis and Systems Intelligence Laboratory, Gif-sur-Yvette, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Thévenot
authors.affiliation: CEA, LIST, Data Analysis and Systems Intelligence Laboratory, Gif-sur-Yvette, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Job
authors.affiliation: CEA, DSV, iBiTecS, Pharmacology and Immunoanalysis Unit, Gif-sur-Yvette, France.
authors.forename: Orianne
authors.initials: O
authors.lastname: Videau
authors.affiliation: Department of Biochemistry, Pharmacogenetics and Molecular Oncology Unit, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.|University Paris Descartes, INSERM UMRS 1147, Sorbonne Paris Cité, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Narjoz
authors.affiliation: Department of Biochemistry, Pharmacogenetics and Molecular Oncology Unit, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.|University Paris Descartes, INSERM UMRS 1147, Sorbonne Paris Cité, Paris, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
authors.affiliation: Department of Biochemistry, Pharmacogenetics and Molecular Oncology Unit, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.|University Paris Descartes, INSERM UMRS 1147, Sorbonne Paris Cité, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.affiliation: Clinical Research Unit EA2706 Paris sud-CHU Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
authors.affiliation: INSERM, IAME, UMR1137, University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.affiliation: Department of Pharmacology and UMR ICAN 1166, Faculty of Medicine, Sorbonne University, UPMC Univ Paris 06, Paris, France.|Department of Pharmacology and CIC-1421, Assistance Publique des Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.affiliation: Clinical Investigation Center (CIC-1425), CHU Bichat Claude Bernard, Paris, France.
authors.forename: Loubna
authors.initials: L
authors.lastname: Alavoine
authors.affiliation: Pharmacy, CHU Bichat Claude Bernard, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Arnaud
authors.affiliation: CEA, DSV, iBiTecS, UMR 8221, Bioenergetics, Structural Biology and Mechanisms Unit, Gif-sur-Yvette, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Delaforge
authors.affiliation: CEA, DSV, iBiTecS, Pharmacology and Immunoanalysis Unit, Gif-sur-Yvette, France. henri.benech@cea.fr.
authors.forename: Henri
authors.initials: H
authors.lastname: Bénech
mesh_terms: D000284:Administration, Oral; D000328:Adult; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010865:Pilot Projects; D055815:Young Adult
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System
keywords: CIME; Pharmacokinetics; Phase I; Probes; Safety