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Once-Daily Darunavir/Ritonavir Keeps Levels High in Healthy Volunteers
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9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
New Orleans
Mark Mascolini
Once-daily darunavir/ritonavir at a dose of 800/100 mg kept darunavir trough concentrations in the safe zone for at least 48 hours among all 7 healthy volunteers who took that dose in a London study [1]. The same dose worked well in the previously reported ARTEMIS trial, which compared darunavir/ritonavir with once- or twice-daily lopinavir/ritonavir in antiretroviral-naive people [2].
Marta Boffito and colleagues at Chelsea and Westminster Hospital recruited 40 volunteers, 34 of them men and 39 of them Caucasian, and assigned them to one of five darunavir/ritonavir doses: 400/100 mg once daily, 800/100 mg once daily, 1200/100 mg once daily, 400/100 mg twice daily, and 800/100 mg once daily. Median age in the five groups ranged from 35 to 44 years. Everyone took both darunavir and ritonavir for 7 days then stopped the darunavir and continued ritonavir for 4 more days.
For all doses the average darunavir trough on treatment day 7 stood above 55 ng/mL, which is the 50% effective concentration of darunavir against nonresistant virus, corrected for protease inhibitor binding to proteins. Darunavir troughs stayed above 55 ng/mL for at least 48 hours after the last dose in all 7 people taking 800/100 mg once daily. Median steady-state darunavir concentration with this dose remained above this threshold for 72 hours after dosing:
· 24 hours after dosing: 1360 ng/mL (range 563 to 1660 ng/mL)
· 36 hours after dosing: 580 ng/mL (range 233 to 850 ng/mL)
· 48 hours after dosing: 181 ng/mL (range 125 to 673 ng/mL)
· 72 hours after dosing: 60 ng/mL (range 27 to 227 ng/mL)
Seven of 40 volunteers (18%) had a grade 2 cholesterol gain while taking darunavir/ritonavir, and 1 of 40 (3%) had a grade 3 cholesterol jump. One person taking 400/100 mg once daily had a grade 3 lipase elevation on day 7 and withdrew from the study on day 12. This person had a grade 1 lipase elevation when screened for the trial.
ARTEMIS researchers randomized 689 antiretroviral-naive people to 800/100 mg of darunavir/ritonavir once daily or to lopinavir/ritonavir, which physicians could prescribe at 400/100 mg twice daily or 800/200 mg once daily [2]. Everyone also took tenofovir/emtricitabine once daily. After 48 weeks a time-to-loss-of-virologic-response analysis determined that 84% taking darunavir and 78% taking lopinavir had a viral load below 50 copies--a result meaning once-daily darunavir is "not noninferior" to either once- or twice-daily lopinavir.
(Many complete slide sets and posters from this workshop will be available at www.hivpresentation.com shortly after the meeting ends.)
References
1. Boffito M, Moyle G, Hill A, et al. The pharmacokinetic profile of darunavir with low-dose ritonavir (DRV/r) in various multiple-dose regimens over 120 hours. 9th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2008. New Orleans. Abstract P31.
2. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at week 48: ARTEMIS (TMC114-C211). 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2007. Chicago. Abstract H-718b.
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