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Efavirenz Lowers Levels of Darunavir Given as 900/100 mg
Once Daily With Ritonavir
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10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
A standard dose of efavirenz significantly lowered darunavir concentrations when healthy volunteers added the nonnucleoside to 900/100 mg of darunavir/ritonavir once daily [1]. Because darunavir's minimum concentration never fell below the 50% effective concentration (EC50) of darunavir for nonresistant virus (55 ng/mL), investigators from the National University of Singapore and Johns Hopkins University in Baltimore suggested this may be a viable regimen for previously untreated people without resistant virus. But they cautioned that their results need to be confirmed in people with HIV.
In a study reported separately by NATAP, this same once-daily dose of darunavir/ritonavir controlled HIV well in 25 people with moderate protease inhibitor (PI) experience and no mutations that make HIV resistant to darunavir [2]. But these researchers did not specify if anyone took efavirenz with darunavir/ritonavir.
Efavirenz induces the CYP3A4 enzyme involved in metabolism of darunavir and ritonavir. As a result, efavirenz lowered darunavir trough concentrations 31% when darunavir/ritonavir was taken at a dose of 300/100 mg twice daily in an earlier study. To test the impact of efavirenz on a 900/100-mg once-daily dose of darunavir/ritonavir, these researchers recruited 12 healthy volunteers in Singapore with weights ranging from 50 to 83 kg and ages from 24 to 49 years. Seven volunteers were men. Everyone took 900/100 mg of darunavir/ritonavir once daily for 10 days, then added 600 mg of efavirenz daily through day 24. Then they stopped the PIs and took only efavirenz from day 25 through 38.
After people added efavirenz to darunavir/ritonavir, darunavir's minimum concentration (Cmin), area under the curve (AUC), and terminal half-life (T1/2), all fell significantly, while oral clearance (CL/F) rose significantly:
⋅ Average Cmin (ng/mL): Before EFV 2137, with EFV 1180, ratio 0.43, P = 0.0003
⋅ Average AUC (hr/ng/mL): Before EFV 103,261, with EFV 89,498, ratio 0.86, P = 0.049
⋅ Average T1/2 (hr): Before EFV 15.3, with EFV 8.5, ratio 0.56, P = 0.00001
⋅ Average CL/F (hr): Before EFV 9657, with EFV 11,392, ratio 1.17, P = 0.047
Ritonavir Cmin, AUC, and T1/2 also dropped significantly when volunteers added efavirenz, and those changes probably affected darunavir values. Efavirenz T1/2 was 66% longer with the PIs than without them (P = 0.01), but efavirenz concentrations did not change after people stopped darunavir/ritonavir.
Grade 3 hepatitis developed in 1 woman and resolved spontaneously after 150 days. One woman had a grade 2 rash and 3 had a grade 1 rash. Triglycerides rose 20% with darunavir and 52% during the PI/efavirenz phase. In an AIDS Clinical Trials Group study of previously untreated people, efavirenz plus lopinavir/ritonavir (and no nucleosides) resulted in significantly more grade 3 or 4 lab toxicity (usually high triglycerides) than either of those drugs plus nucleosides [3].
Because darunavir minimum concentrations remained above the EC50 for nonresistant virus with efavirenz in the Singapore study, the researchers suggested this regimen may be effective for previously untreated people with no PI or nonnucleoside resistance mutations. But they cautioned that the clinical significance of the interaction they discovered must be explored in people with HIV.
References
1. Lee LS, Soon GH, Shen P, Flexner C, Pham P. Pharmacokinetics of darunavir 900mg and ritonavir 100 mg (DRV/rtv) once daily when co-administered with efavirenz 600mg once daily in healthy adult volunteers. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_29.
2. Curran A, Gutierrez M, Lopez R, et al. Pharmacokinetics, efficacy and safety of darunavir/ritonavir 900/100 mg once-daily. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_14.
3. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358:2095-2106.
Ripamonti D, Maggiolo F, d'Avolio A, et al. Steady-state pharmacokinetics of Atazanavir (200mg BID) when combined with Raltegravir (400mg BID) in HIV-1 infected adults.
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