Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * 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. WHAT THIS STUDY ADDS: * 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. AIMS: 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. CONCLUSION: The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug-drug interactions in vivo.

The pharmacokinetics of fondaparinux sodium in healthy volunteers.

OBJECTIVE: Fondaparinux sodium is the first in a new class of synthetic factor Xa inhibitors that binds reversibly with high affinity to antithrombin III. It has been investigated for the prevention and treatment of arterial and venous thrombotic disorders and approved for use at a dose of 2.5mg once daily in the prevention of venous thromboembolism in major orthopaedic surgery. The pharmacokinetics of fondaparinux sodium were determined in eight studies in young and elderly healthy volunteers. RESULTS: After a 2.5mg subcutaneous dose to young volunteers, absolute bioavailability was 100% and absorption was rapid and complete [peak plasma concentration (C(max)) 0.34 mg/L occurred at approximately 2 hours]. Within- and total-subject variability estimates were small: 5.5 and 11.6%, respectively, for C(max )and 4.4 and 17.5% for area under the concentration-time curve (AUC). Steady state was obtained after the third or fourth once-daily dose, with a 1.3-fold increase in C(max) and AUC. Distribution volume (7 to 11L) was limited to blood volume. There was no evidence of metabolism. Fondaparinux sodium was almost completely excreted in urine as unchanged compound (64 to 77% of the dose was recovered at 72 hours after administration). Plasma clearance was 5.1 to 7.9 ml/min, renal clearance 4.0 to 7.9 ml/min, and the terminal half-life was 17 hours in young volunteers and 21 hours in elderly volunteers. Pharmacokinetics of fondaparinux sodium were linear in the range 2 to 8mg subcutaneously and 2 to 20mg intravenously. Pharmacokinetics observed in healthy elderly volunteers were consistent with findings in young male volunteers. CONCLUSION: The favourable pharmacokinetic profile of fondaparinux sodium is likely to play an important role in the major advance that the drug represents in the prevention and treatment of thrombotic disorders.

Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers.

OBJECTIVE: Patients undergoing major orthopaedic surgery who are being treated with fondaparinux sodium for prevention of venous thromboembolism may be receiving treatment for coronary artery disease or chronic inflammatory disease of the joints or arthritis. Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers. DESIGN: In the first study a single dose of aspirin 975mg was assessed initially, followed by single doses of aspirin or placebo on the fourth day of an 8-day regimen of subcutaneous fondaparinux sodium (10mg once daily). The second study was a three-way crossover, double-blind, randomised study which investigated fondaparinux sodium 10mg + placebo, fondaparinux sodium 10mg + piroxicam 20mg, or placebo + piroxicam 20mg. METHODS: Both studies obtained plasma concentration-time profiles of fondaparinux sodium administered alone and with aspirin or piroxicam. Noncompartmental parameters - peak concentration, trough concentration, time to reach peak concentration, and area under the concentration-time curve - were obtained. Both studies measured the pharmacodynamic parameters bleeding time and activated partial thromboplastin time (aPTT). Safety was monitored. RESULTS AND CONCLUSIONS: Neither aspirin nor piroxicam influenced the pharmacokinetics of fondaparinux sodium at steady state. Two hours after administration, prolongation of bleeding time with aspirin alone or with aspirin plus fondaparinux sodium was significantly greater than with fondaparinux sodium alone (p = 0.003 and p = 0.004, respectively). No significant differences were observed between aspirin alone or aspirin + fondaparinux sodium in effect on bleeding time. A small decrease in collagen-induced platelet aggregation was observed after administration of piroxicam alone or piroxicam + fondaparinux sodium. A small effect on aPTT was observed; it was similar for fondaparinux sodium whether administered alone or in combination with either aspirin or piroxicam. No serious adverse events were reported.