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Fosamprenavir/RTV Cuts Dolutegravir Levels:
No Dose Change Needed for Naive
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Fosamprenavir/ritonavir lowered concentrations of the integrase inhibitor dolutegravir, decreasing dolutegravir trough levels almost 50%, in a study involving healthy HIV-negative volunteers [1]. But dolutegravir concentrations remained well above the protein binding-adjusted 90% inhibitory concentration for wild-type (nonmutant) virus, so the investigators concluded that no dose adjustment is needed for people taking dolutegravir as their first integrase inhibitor.
Dolutegravir, now in phase 3 trials in antiretroviral-naive and experienced people, has activity against virus resistant to raltegravir, the only licensed integrase inhibitor. The investigational drug can be taken once daily without a boosting agent. Because dolutegravir is metabolized by UGT1A1 and CYP3A and because fosamprenavir/ritonavir induces or inhibits these enzymes, researchers planned this single-center, open-label, single-sequence study involving 12 healthy adults without HIV.
Ritonavir's strong inhibition of CYP3A4 explains its boosting effect on other protease inhibitors (PIs) and other drugs metabolized by that enzyme. So other ritonavir-boosted PIs are likely to affect dolutegravir concentrations. Other strong CYP3A4 inhibitors include the antibiotics clarithromycin and chloramphenicol and the antifungals ketoconazole and itraconazole.
Study participants took 50 mg of dolutegravir once daily for 5 days then added 700/100 mg of fosamprenavir/ritonavir twice daily for 10 days. Volunteers took all doses after a 10-hour overnight fast. The investigators collected serial samples on days 5 and 15 to measure dolutegravir and amprenavir levels.
The 12 healthy volunteers were 10 men and 2 women, including 5 nonwhites. Their age averaged 33.4 years (+/- 11.8) and their body mass index 25.6 kg/m(2) (+/- 4.0). All 12 participants completed the study. There were no grade 2, 3, or 4 adverse events, no serious adverse events, and no clinically significant trends in lab values, vital signs, or ECGs. Two people had any adverse event during treatment with dolutegravir alone, one with insomnia and one with abnormal dreams. During treatment with dolutegravir plus fosamprenavir/ritonavir, 5 people had any adverse event: 2 with rash and 1 each with abnormal dreams, headache, nausea, or oral paresthesia (tingling or numbness).
Amprenavir levels were similar to those reported earlier in other studies of fosamprenavir. Compared with dolutegravir concentrations when the integrase inhibitor was taken alone, concentrations with fosamprenavir/ritonavir were substantially lower. Area under the concentration-time curve (AUC) was 35% lower, maximum concentration (Cmax) 24% lower, and trough concentration (Ctrough) 49% lower, as indicated by the following geometric least squares (GLS) mean ratios for dolutegravir plus fosamprenavir/ritonavir versus dolutegravir alone:
GLS mean ratios (and 90% confidence intervals)
-- AUC 0.651 (0.542 to 0.782)
-- Cmax 0.763 (0.632 to 0.921)
-- Ctrough 0.510 (0.413 to 0.629)
The researchers concluded that "no dose adjustment is needed when dolutegravir is co-administered with fosamprenavir/ritonavir in integrase inhibitor-naive" people.
Reference
1. Song I, Borland J, Chen S, et al. Effect of fosamprenavir/ritonavir on the pharmacokinetics of the integrase inhibitor, dolutegravir, in healthy subjects. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract A1-1727.
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