The effect of single‐and multiple‐dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects.
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Study Design
The pharmacokinetic interaction potential of triazolam and etravirine has not been studied, but inferences can be made using studies that describe the interaction between midazolam and etravirine. 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.
Study Results
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]).
Study Conclusions
These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P‐glycoprotein activity. The clinical significance of these findings is unknown. Midazolam should be used cautiously with etravirine. Switch to alternative benzodiazepines may be preferred.
References
Kakuda TN, Solingen Ristea V, Rodica M, Onkelinx J, Stevens T, Aharchi F, Hoetelmans R. The effect of single‐and multiple‐dose etravirine on a drug cocktail of representative cytochrome p450 probes and digoxin in healthy subjects. The Journal Of Clinical Pharmacology . 2014; 4: 422-431.
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