warfarin and 1-7-dimethylxanthine

A 100-fold uncertainty factor is used to derive acceptable daily intakes for compounds causing thresholded toxicity. The 10-fold factor for human variability can be further subdivided into two factors of 10(0.5) (3.16) to allow for toxicokinetics and toxicodynamics. The validity of the human kinetic subfactor has been analysed in relation to CYP1A2 metabolism using published in vivo pharmacokinetic parameters selected to reflect chronic exposure (metabolic and total clearances and area under the plasma concentration-time curve: CLm, CL and AUC) and acute exposure (the peak plasma concentration, C(max)). The variability in CYP1A2 activity in healthy adults, based on data after oral and intravenous dosage (CLm, CL and AUC), ranged from 34 to 42%. The variability in C(max) was 21%. The default kinetic factor of 3.16 would cover at least 99% of the healthy adult population, assuming that the data were log-normally distributed, but would give lower protection for some subgroups (pregnant women at term, healthy elderly, patients with liver disease), and was inadequate for neonates. This analysis of in vivo kinetic data for CYP1A2 substrates illustrates the importance of quantifying human variability in specific metabolic pathways, and of identifying potentially susceptible subgroups of the human population, in order to determine the scientific validity of uncertainty factors.

Topics: Adult; Aged; Area Under Curve; Caffeine; Child; Cytochrome P-450 CYP1A2; Humans; Infant, Newborn; Models, Biological; Pharmacokinetics; Probability; Reproducibility of Results; Risk Assessment; Substrate Specificity; Theobromine; Theophylline; Warfarin

The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.

Topics: Adolescent; Adult; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caffeine; Cross-Over Studies; Cytochrome P-450 Enzyme System; Dextromethorphan; Digoxin; Female; Healthy Volunteers; Humans; Male; Midazolam; Middle Aged; Nitriles; Omeprazole; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Theophylline; Warfarin; Young Adult