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  13th International Workshop on Clinical Pharmacology of HIV Therapy
Barcelona, Spain
April 16-18, 2012
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Etravirine Levels 25% Lower With HCV Protease Inhibitor Boceprevir
  13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Concentrations of the nonnucleoside etravirine were unexpectedly about 25% lower with than without the HCV protease inhibitor boceprevir in a study of 26 healthy volunteers [1]. Changes in boceprevir levels were more modest when the anti-HCV drug was taken with etravirine, but those changes also ran contrary to expectation.
Previous research found that boceprevir lowers exposure of ritonavir-boosted atazanavir, darunavir, and lopinavir [2], a finding that led the FDA to advise close monitoring of patients already taking boceprevir with a boosted PI [3].
Both boceprevir and etravirine are CYP3A substrates, meaning CYP3A enzymes can act on both drugs: Etravirine (like other nonnucleosides) is a CYP3A inducer, while boceprevir is partly metabolized by CYP3A4 and CYP3A5 and is a strong CYP3A4 and CYP3A5 inhibitor. To investigate possible interactions between these antivirals, University of Colorado researchers planned this study in healthy volunteers without HIV or HCV infection. On the basis of previous data, they hypothesized that (1) boceprevir concentrations will be lower with than without etravirine and (2) etravirine concentrations will be higher with than without boceprevir.
The study enrolled 26 adults, who took three regimens: (1) boceprevir at a dose of 800 mg every 8 hours, (2) etravirine at 200 mg every 12 hours, and (3) boceprevir plus etravirine at those doses. The investigators randomized participants to take the regimens in different sequences, with a 14-day no-drug washout between each 11- to 14-day course. The researchers collected samples to measure drug concentrations on days 11 to 14 after they watched volunteers take the drugs with a standardized meal.
Of the 26 people enrolled, 20 completed all three sequences. Ten of the 20 were women; 14 were white, 3 black, and 3 Hispanic. Median age and weight were 36 years and 73 kg.
Of the 6 people who dropped out of the study, 4 quit because of grade 2 rash (3 during combination treatment and 1 on etravirine alone), 1 quit because of anxiety and insomnia while taking both drugs, and 1 quit because a presumed viral illness during combination treatment made her miss 3 days of dosing. Altered taste affected 18 of 21 people when they were taking boceprevir alone and 16 of 25 people when they were taking boceprevir and etravirine.
Contrary to one of the study hypotheses, geometric mean etravirine concentrations were higher when the nonnucleoside was taken alone than when taken with boceprevir:
Etravirine geometric mean concentrations (and coefficient of variation): -- AUCtau: 7698 ng*hr/mL (33) alone versus 5957 ng*hr/mL (54) with boceprevir -- Cmax: 900 ng/mL (29) alone versus 686 ng/mL (45) with boceprevir -- Cmin: 439 ng/mL (46) alone versus 313 ng/mL (60) with boceprevir
(AUCtau is area under the concentration-time curve over the dosing interval, Cmax is maximum concentration, and Cmin is minimum concentration.)
Geometric mean ratios (and 90% confidence intervals) for etravirine with boceprevir versus etravirine alone were 0.77 (0.66-0.91) for AUCtau, 0.76 (0.68-0.85) for Cmax, and 0.71 (0.54-0.95) for Cmin, meaning those etravirine concentrations were 23%, 24%, and 29% lower with boceprevir than without boceprevir.
Also contrary to one of the study hypotheses, geometric mean boceprevir concentrations varied in an inconsistent pattern with and without etravirine:
Boceprevir geometric mean concentrations (and coefficient of variation): -- AUCtau: 4601 ng*hr/mL (47) alone versus 5047 ng*hr/mL (30) with etravirine -- Cmax: 1423 ng/mL (43) alone versus 1565 ng/mL (28) with etravirine -- 8-hour concentration: 106 ng/mL (64) alone versus 94 ng/mL (98) with etravirine
Geometric mean ratios (and 90% confidence intervals) for boceprevir with etravirine versus boceprevir alone were 1.10 (0.94-1.28) for AUCtau, 1.10 (0.94-1.29) for Cmax, and 0.88 (0.66-1.17) for 8-hour concentration, meaning AUCtau and Cmax were 10% higher with etravirine, while the 8-hour concentration was 12% lower with etravirine.
The investigators noted that "the observed interactions were not predicted based on our current knowledge of the pharmacology of these drugs." They cautioned that "interactions between boceprevir and antiretroviral drugs are complex and additional research is needed to elucidate their mechanism(s) and therapeutic implications." Although changes in etravirine concentrations with boceprevir lay within the bounds of clinical relevance, the researchers noted that these changes could reach clinical relevance in clinical practice, when an array of additional factors may be at play.
1. Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV seronegative volunteers. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_15.
2. Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 771LB. http://www.natap.org/2012/CROI/croi_20.htm.
3. US Food and Drug Administration. FDA drug safety communication: important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. February 8, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm291119.htm.