Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV seronegative volunteers.
OBJECTIVE
The primary aim of this study was to determine the bioequivalence of boceprevir, an HCV protease inhibitor and etravirine, an HIV non-nucleoside reverse transcriptase inhibitor; area under the concentration time curve (AUC(0,τ)); maximum concentration (C(max)); and trough concentration (C(8) or C(min)) when administered in combination versus alone.


METHODS
Open-label crossover study in healthy volunteers.


METHODS
Boceprevir, etravirine, and the combination were administered for 11-14 days with intensive sampling between days 11 and 14 of each sequence. Boceprevir and etravirine were quantified using validated liquid chromatography coupled with tandem mass spectrometry and high-performance liquid chromatography/ultraviolet assays, respectively and pharmacokinetics determined using noncompartmental methods. Geometric mean ratios (GMRs) and 90% confidence interval (CI) for the combination versus each drug alone were evaluated using 2 one-sided t tests. The hypothesis of equivalence was rejected if 90% GMR CI was not contained in the interval (0.8-1.25).


RESULTS
Twenty subjects completed study. GMRs (90% CI) for etravirine AUC(o,τ), C(max), and C(min) were 0.77 (0.66 to 0.91), 0.76 (0.68 to 0.85), and 0.71 (0.54 to 0.95), respectively, in combination versus alone. Boceprevir GMRs (90% CI) for AUC(o,τ), C(max), and C(8) were 1.10 (0.94 to 1.28), 1.10 (0.94 to 1.29), and 0.88 (0.66 to 1.17), respectively, in combination versus alone. All adverse events (n = 112) were mild or moderate. Six subjects discontinued: 4 due to rash, 1 due to central nervous system effects, and 1 for a presumed viral illness.


CONCLUSIONS
Etravirine AUC(o,τ), C(max), and C(min)decreased 23%, 24%, and 29%, respectively, with boceprevir. Boceprevir AUC(0,τ) and C(max) increased 10% and C(8) decreased 12% by etravirine. Additional research is needed to elucidate the mechanism(s) and therapeutic implications of the observed interaction.
School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA.
Kyle P
KP
Hammond
Pamela
P
Wolfe
James R
JR
Burton
Julie A
JA
Predhomme
Christine M
CM
Ellis
Michelle L
ML
Ray
Lane R
LR
Bushman
Jennifer J
JJ
Kiser
D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010949:Plasma / Q000737:chemistry; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011724:Pyridazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011743:Pyrimidines; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000998:Antiviral Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline