Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir.
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Study Design
In a randomized, open label trial conducted in 39 healthy adults, Hulskotte, et al1 assessed the pharmacokinetic interactions between boceprevir (BOC) and ritonavir boosted protease inhibitors atazanavir, darunavir and lopinavir. Subjects received 800 mg of boceprevir three times daily for six days and then, from days 10 – 31, received one of three boosted protease inhibitor regimens: atazanavir 300 mg daily, darunavir 600 mg twice daily and lopinavir 400 mg twice daily, each with 100 mg of ritonavir with every dose of HIV-1 protease inhibitor (ie, once daily with atazanavir, and twice daily with darunavir and lopinavir). From days 25 – 31, boceprevir 800 mg every eight hours was given in addition to the ritonavir boosted protease inhibitor. Blood samples for BOC pharmacokinetic analysis were collected predose on the mornings of days 4, 5, and 6, and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on day 6. Blood samples for assessment of PI/r pharmacokinetics were taken predose on days 10, 18, 23, 28, and 29, and postdose on days 24 and 30 at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours, and also at 24 hours postdose in patients receiving ATV/r (ATV/r only). Additional blood samples to assess BOC pharmacokinetics were collected predose on days 29 and 30 and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on day 31. To account for the effect of food on PK values, standard breakfasts were utilized for all patients on days where PK sampling was done.
Study Results
Mean concentrations of lopinavir were decreased at all points in which the ritonavir boosted medication was given with boceprevir. Geometric mean ratios for LPV AUC0-last, Cmax, and Cmin were reduced 34%, 30%, and 43%, respectively, in the presence of BOC plus LPV/r, compared with LPV/r alone. Geometric mean LPV Cmin was decreased from 6730 ng/mL to 3805 ng/ mL by the presence of BOC. This combination also reduced concentrations of boceprevir, as AUCt, Cmax, and Cmin GMRs decreased between 45% and 57% when BOC was coadministered with LPV/r. Geometric least-squares mean BOC Cmin decreased from 92 ng/mL to 40 ng/mL with LPV/r coadministration.
The authors posited that these complex interactions cannot be explained simply by CYP3A interactions, but may also involve an interplay between efflux transport proteins or the role of protein displacement or altered absorption.
Study Conclusions
An FDA alert was issued in response to new pharmacokinetic data from Merck the manufacturer of boceprevir. The company conducted a drug interaction study on concomitant administration of boceprevir with ritonavir-boosted atazanavir, darunavir or lopinavir/ritonavir. Per the manufacuter, boceprevir reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir, and darunavir by 49, 43 and 59 percent, respectively. Also, mean reductions of 34 to 44 percent and 25 to 36 percent were observed in the AUC and Cmax of atazanavir, lopinavir, and darunavir. The AUC of boceprevir was not affected when co-administered with ritonavir-boosted atazanavir. However, the AUC of boceprevir was decreased by 45% and 32% when co-administered with lopinavir/ritonavir and ritonavir-boosted darunavir, respectively. The concomitant administration of these medications has the potential to reduce the effectiveness of these agents.
References
Hulskotte EG, Feng HP, Xuan F, van Zutven MG, Treitel MA, Hughes EA, Butterton JR. Pharmacokinetic interactions between the hepatitis c virus protease inhibitor boceprevir and ritonavir-boosted hiv-1 protease inhibitors atazanavir, darunavir, and lopinavir. Clinical Infectious Diseases. 2012; 5: 718-726.
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