Pharmacokinetic and pharmacodynamic assessment of a five-probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1.
OBJECTIVE
The primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed.


METHODS
Twelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full "cocktail" as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUClast (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events


RESULTS
Overall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone.


CONCLUSIONS
The five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically important drug-drug interactions during drug development.
Blakey
G E
GE
Department of Experimental Medicine, AstraZeneca R & D, Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK. graham.blakey@astrazeneca.com
Lockton
J A
JA
Perrett
J
J
Norwood
P
P
Russell
M
M
Aherne
Z
Z
Plume
J
J
D000328:Adult; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002753:Chlorzoxazone / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D003647:Debrisoquin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D010949:Plasma; D014044:Tolbutamide / Q000493:pharmacokinetics / Q000494:pharmacology*
D004338:Drug Combinations; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D002753:Chlorzoxazone; D008874:Midazolam; D003647:Debrisoquin