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Darunavir/Cobicistat Formulation Yields Darunavir Level Close to Darunavir/Ritonavir
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April
16-18, 2012, Barcelona
Mark Mascolini
Two once-daily fixed-dose formulations of darunavir with the boosting agent cobicistat (800/150 mg) proved similar to darunavir/ritonavir (800/100 mg) in resulting darunavir concentrations in a study of healthy volunteers [1]. Although darunavir minimum concentrations with darunavir/cobicistat were lower than with darunavir/ritonavir, the Janssen investigators believe that difference has no clinical relevance.
Cobicistat, which boosts levels of CPY3A substrates such as HIV protease inhibitors (PIs), is being evaluated in fixed-dose formulations with the integrase inhibitor elvitegravir [2] and the PI atazanavir [3].
The new study by Janssen researchers enrolled 36 HIV-negative healthy adults who sequentially took darunavir/ritonavir (at 800/100 mg once daily) and each of the two darunavir/cobicistat formulations (G003 and G004 at 800/150 mg once daily) for 10 days, with the order of courses randomized and each course separated by at least 7 days taking no drugs. The investigators drew blood samples over 24 hours on day 10 of each dosing interval. They compared darunavir concentrations with cobicistat versus ritonavir by least square means ratios and 90% confidence intervals.
The pharmacokinetic analyses included 33 people taking G003, 33 taking G004, and 32 taking darunavir/ritonavir. Safety analyses included 35 volunteers taking G003, 34 taking G004, and 34 taking darunavir/ritonavir.
The investigators detected no serious adverse events or lab abnormalities in any study participant. Five people dropped out of the study because of an adverse event: Rash was the problem in all 5 people, including 2 taking darunavir/G003, 1 taking darunavir/G004, and 2 taking darunavir/ritonavir. Three grade 3 adverse events occurred, including one episode of fatigue with darunavir/ritonavir, one rash with darunavir/G003, and one rash with darunavir/G004. Nausea and diarrhea arose with similar frequency with all three treatments.
Least square mean ratios indicated virtually identical darunavir maximum concentration (Cmax) and 24-hour area under the concentration-time curve (AUC) with darunavir/G003 and darunavir/ritonavir (0.97 for Cmax and 0.97 for 24-hour AUC) and with darunavir/G004 and darunavir/ritonavir (1.00 for Cmax and 0.99 for 24-hour AUC). The 90% confidence intervals for those comparisons were all within 80% to 125%, which indicates bioequivalence.
Darunavir minimum concentrations were 31% lower with G003 than with ritonavir (least square means ratio 0.69, 90% CI 0.60 to 0.81) and 26% lower with G004 than with ritonavir (least square means ratio 0.74, 90% CI 0.63 to 0.86).
On the basis of limited data on darunavir troughs below 550 ng/mL and modeling studies that suggest no loss of antiviral activity with a 50% drop in trough, the researchers do not consider these moderately lower darunavir troughs with cobicistat to be clinically relevant. However, they do fall outside the generally accepted bioequivalence range of 80% to 125%. Jonathan Schapiro, an antiretroviral expert and clinician, proposed that the burden of proof remains on the manufacturer to show that this drop in darunavir trough is not clinically meaningful. Drug levels can vary considerably from person to person, he noted, so for some individuals a 25% or 30% lower trough may be meaningful.
Janssen investigators selected the G004 formulation for further development.
References
1. Kakuda TN, Opsomer M, Timmers M, et al. Bioavailability of two FDC formulations of darunavir/cobicistat 800/150mg compared with darunavir/ritonavir 800/100mg co-administered as single agents. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_20.
2. Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011;25:F7-F12.
3. Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. AIDS. 2011;25:1881-1886.
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