Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

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.