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Low Darunavir Troughs at 800 Mg Once Daily With Stribild
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16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Darunavir trough concentrations slipped into the subtherapeutic zone when 8 people with heavy antiretroviral experience took the protease inhibitor (PI) at 800 mg once daily with Stribild (coformulated elvitegravir, cobicistat, tenofovir, and emtricitabine) [1]. Although 7 people maintained an undetectable viral load, viral blips suggested the regimen may be fragile in some.
Stribild is licensed as a once-daily combination for antiretroviral-naive people or those with an undetectable viral load on a stable regimen taken for at least 6 months [2]. Product information advises against combining Stribild with other antiretrovirals [2]. Yet some clinicians add darunavir to Stribild as a simple once-daily regimen for people with antiretroviral experience and resistant virus. Some countries have licensed 800/150 mg of darunavir/cobicistat as a one-pill once-daily agent (Prezcobix in the United States). Stribild also contains 150 mg of cobicistat, a strong CYP3A inhibitor.
McGill University researchers and collaborators from other sites retrospectively assessed virologic response and darunavir pharmacokinetics in 8 people who had drug concentrations measured at least once while taking 800 mg of darunavir once daily plus Stribild. When samples were collected more than 10 hours after dosing, the researchers extrapolated the darunavir trough concentration by using the average darunavir elimination half-life of 7.57 h for darunavir plus elvitegravir/cobicistat. For people with darunavir-specific mutations, the McGill team targeted a genotypic inhibitory quotient of 2.15 mg/L/mutation. In people without darunavir mutations, the investigators selected a darunavir trough target of 0.17 mg/L or more, which is 3 times the protein binding-adjusted 50% inhibitory concentration for wild-type (nonmutant) virus (0.055 mg/L).
The 8 study participants had taken a median of 9 antiretroviral regimens; 7 people had a virologic failure with a PI regimen. Only one person had virus with a darunavir-specific mutation (33F). When antiretroviral concentrations were first measured, 7 of 8 people had an undetectable viral load. All 8 study participants reported 100% adherence to the regimen.
The pharmacokinetic analysis involved 23 samples collected an average 17.5 hours after dosing. Samples collected during the antiretroviral absorption phase indicated optimal absorption. Among samples collected during the elimination phase, median darunavir trough stood at 0.273 mg/L (interquartile range 0.164 to 0.501), which is 80% lower than a historical population median of 1.36 mg/L with 800/100 mg of darunavir/ritonavir once daily. In 2 people who had drug concentrations measured while taking darunavir/ritonavir before switching to Stribild, darunavir troughs fell by 25% and 83% after the switch.
Genotypic inhibitory quotient for the 1 person with darunavir-resistant virus stood at 0.34 mg/L/mutation, far below the 2.15-mg target. Among all darunavir levels measured, 52.6% were considered subtherapeutic. Two people had their darunavir dose boosted to 1200 mg daily and saw no substantial improvement in darunavir trough. One person switched to 600 mg of darunavir twice daily plus a second 150-mg cobicistat boost and reached a therapeutic genotypic inhibitory quotient of 5.37 mg/L/mutation.
At the time of this report, 7 of 8 people maintained an undetectable viral load, though 3 had viral blips. Those blips, the researchers suggested, "indicate that low darunavir concentrations might hinder durability of virologic suppression." They recommended close monitoring of people taking this regimen and switching to another regimen if blips occur.
The researchers hypothesized that lower than expected darunavir troughs in these people could reflect induction of cobicistat metabolism by darunavir and elvitegravir and thus insufficient CYP3A4 inhibition by cobicistat at the end of the dosing interval. Alternatively, they suggested, cobicistat and ritonavir may yield similar intestinal CYP3A4 inhibition, but hepatic inhibition could be lower with cobicistat.
References
1. Ricard F, Wong A, Lebouche B, et al. Low darunavir concentrations in patients receiving Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) and darunavir once daily. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 50.
2. Stribild product information. https://www.stribild.com/hcp
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