Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A.
BACKGROUND
* Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug-drug interactions in vivo. * This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions.


CONCLUSIONS
* This study describes a new cocktail containing five probe drugs that has never been published. * This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails.


OBJECTIVE
To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.


METHODS
This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg(-1) midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed C(max), AUC(last) and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte C(max), AUC(last) and AUC.


RESULTS
There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.


CONCLUSIONS
The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug-drug interactions in vivo.
Turpault
Sandrine
S
Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern, PA, USA. sandrine.turpault@sanofi-aventis.com
Brian
William
W
Van Horn
Robert
R
Santoni
Alix
A
Poitiers
Franck
F
Donazzolo
Yves
Y
Boulenc
Xavier
X
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
D014151:Anti-Anxiety Agents; D000897:Anti-Ulcer Agents; D000925:Anticoagulants; D000697:Central Nervous System Stimulants; D004338:Drug Combinations; D002110:Caffeine; D014859:Warfarin; D019388:Cytochrome P-450 CYP1A2; D009853:Omeprazole; D008874:Midazolam