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Rifabutin Cuts Elvitegravir Levels, But No Critical Elvitegravir Interactions With Atazanavir or Rosuvastatin
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Elvitegravir, the experimental integrase inhibitor, should not (for now) be given with the anti-TB drug rifabutin, even at a lower-than-normal rifabutin dose, according to results of a study in healthy volunteers [1]. But the same study saw no major interactions between elvitegravir and rosuvastatin, which is not metabolized via CYP3A enzymes, or between elvitegravir and the protease inhibitor atazanavir.
Coformulated elvitegravir/cobicistat plus tenofovir/emtricitabine, called QUAD, proved virologically noninferior to Atripla in the first phase 3 trial comparing two single-pill, once-daily combination antiretrovirals [2]. Serum creatinine initially rose with QUAD then leveled off, but at week 48 the serum creatinine change was significantly greater with QUAD than with Atripla (efavirenz plus tenofovir/emtricitabine): +0.14 versus +0.01 mg/dL (P < 0.001).
The pharmacokinetic study involved three sets of healthy adults who took elvitegravir/cobicistat, atazanavir, rosuvastatin, and rifabutin in various sequences [1]. Because cobicistat is designed to interact with CYP3A, the investigators chose to assess a statin not metabolized via that pathway.
Cohort 1: 12 volunteers took a single dose of rosuvastatin; elvitegravir/cobicistat at 85/150 mg plus atazanavir at 300 mg once daily for 10 days; elvitegravir/cobicistat at 150/150 mg once daily for 10 days; elvitegravir/cobicistat at 150/150 mg once daily plus rosuvastatin at 10 mg.
Cohort 2: 10 volunteers took elvitegravir/cobicistat at 85/150 mg plus atazanavir at 300 mg once daily for 10 days; then atazanavir at 300 mg plus ritonavir at 100 mg once daily for 10 days.
Cohort 3: 12 volunteers took elvitegravir/cobicistat at 150/150 mg once daily for 10 days followed sequentially by 13 days of elvitegravir/cobicistat plus rifabutin at 150 mg every other day, a 10-day washout, then 13 days of rifabutin at 300 mg once daily.
Five of 34 volunteers (15%) dropped out of the study because of adverse events, 2 when taking elvitegravir/cobicistat plus atazanavir in Cohort 1 and 3 when taking elvitegravir/cobicistat plus atazanavir in Cohort 2. Three dropouts resulted from grade 3 hyperbilirubinemia, a side effect typically caused by atazanavir. One person left the study because of grade 3 rash and one because of grade 2 abdominal pain; both people also had grade 2 or 3 hyperbilirubinemia. Besides high bilirubin, the most common adverse events were headache and constipation. All side effects resolved during the course of the study. There were no grade 4 or serious adverse events.
Rosuvastatin did not affect elvitegravir exposure, but coadministration of elvitegravir/cobicistat resulted in and 89% higher rosuvastatin maximum concentration (Cmax) (geometric mean ratio [GMR] 189, 90% confidence interval [CI] 148 to 242) and a 38% higher rosuvastatin area under the concentration-time curve (AUC) (GMR 138, 95% CI 114 to 167). The Gilead investigators characterized these changes as not clinically relevant.
When given with elvitegravir/cobicistat, atazanavir Cmax was 24% lower (GMR 76.1, 90% CI 59.1 to 96.9), and atazanavir trough concentration was almost 20% lower (GMR 80.5, 90% CI 55.6 to 117). But the atazanavir trough remained well above the atazanavir protein binding-adjusted 95% inhibitory concentration for wild-type virus. Coadministration of atazanavir did not have a large impact on elvitegravir concentrations.
Dosing rifabutin with elvitegravir/cobicistat resulted in a 67% lower elvitegravir trough (GMR 32.9, 90% CI 26.9 to 40.10). Elvitegravir/cobicistat did not dramatically affect rifabutin exposure, but coadministration of the drugs resulted in 4.8- to 6.3-fold higher levels of the rifabutin metabolite 25-O-desacetylrifabutin. The investigators calculated 21% higher total antimycobacterial activity of rifabutin upon codosing with elvitegravir/cobicistat.
The Gilead team concluded that the modestly higher rosuvastatin exposures with elvitegravir/cobicistat do not require dose adjustments. But HIV pharmacologist David Burger (St. Radboud University Medical Center, Nijmegen) wondered whether it may be premature to characterize these interactions confidently on the basis of a small study in healthy volunteers.
The Gilead investigators concluded that neither rosuvastatin nor atazanavir affects elvitegravir concentrations. But they determined that "coadministration of elvitegravir with dose-reduced rifabutin is not recommended due to a reduction in elvitegravir Ctrough." They added, though, that elvitegravir troughs with rifabutin fell within the range of the bottom quartile in phase 3 trials (45 to 318 ng/mL).
References
1. Ramanathan S, Wang H, Stondell T, Cheng A, Kearney B. Pharmacokinetics and drug interaction profile of cobicistat boosted-EVG with atazanavir, rosuvastatin or rifabutin. 13th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2012. Barcelona. Abstract: O_03.
2. Sax P, DeJesus E, Mills A, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate has non-inferior efficacy and favorable safety compared to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1+ subjects. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 101. http://www.natap.org/2012/CROI/croi_58.htm.
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