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.

Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug‐Drug Interaction Evaluation: Perspectives From the International Transporter Consortium

“…The cocktail approach has been successfully applied in drug development and recognized by regulatory agencies to assess DDIs with CYP enzymes . However, the evaluation and use of dedicated drug cocktails to study transporter‐related DDIs is still limited . In 2011, Maeda et al .…”

Design optimisation for pharmacokinetic modeling of a cocktail of phenotyping drugs

“…The phenotyping cocktail strategy is of high interest to determine the activity of enzymes responsible for drug metabolism and pharmacokinetics (PK) . It consists of simultaneously phenotyping several cytochromes P450 (CYP) and transporters using a mixture of selective substrates, for example, the Cooperstown cocktail or the CIME (Metabolic Identity Card) combination . The principle of the phenotyping tests is to administer the cocktail in individuals, collect an adequate number of plasma samples, quantify the substrates and metabolites, and analyze the data in order to estimate phenotyping indexes (PI) of individuals.…”

“…Here we chose to focus on a combination of two molecules, digoxin and midazolam, which are well‐known probes for P‐glycoprotein (P‐gp) function and CYP3A activity, respectively, as a large number of existing drugs are substrates of either P‐gp or CYP3A or both . Joint mathematical substrate/metabolite models and NLMEM were used to get a priori information on digoxin, midazolam and its metabolite 1‐OH‐midazolam from a pilot phase‐I study (CIME1) . For ethical and practical reasons, identical sparse samples must be considered for substrate and metabolite concentration measurements of both drugs.…”

No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P‐glycoprotein

“…Cocktail approaches for phenotyping involving the administration of multiple CYP‐specific or P‐gp‐specific probe drugs were used to simultaneously assess the activities of these enzymes and the transporter P‐gp. Many phenotyping cocktails have been developed and used in recent years . For this study, the compilation of the probe drugs was selected according to a validated phenotyping cocktail (Geneva cocktail), which also included a probe drug for P‐gp (fexofenadine).…”

“…Many phenotyping cocktails have been developed and used in recent years. [20][21][22][23][24][25] For this study, the compilation of the probe drugs was selected according to a validated phenotyping cocktail (Geneva cocktail 26,27 ), which also included a probe drug for P-gp (fexofenadine). To our knowledge, this is the first seven-probe drug cocktail interaction study investigating St. John's wort.…”