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Food and Fat Have Little Impact on Dolutegravir, a New Integrase Inhibitor
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Regardless of fat content, food modestly boosted exposure of dolutegravir (S/GSK1349572), an experimental integrase inhibitor, in healthy volunteers [1]. ViiV Healthcare researchers concluded that, if licensed, "dolutegravir can be given with or without food and without regard to fat content."
Dolutegravir is in late-stage development for treatment of antiretroviral-naive and experienced people [2,3]. To gauge the impact of food on dolutegravir concentrations, ViiV researchers planned this randomized, open-label study involving 18 healthy adults without HIV. Study participants took a single 50-mg dose of dolutegravir on four separate occasions separated by 7 days: fasting, with a low-fat meal (300 kcal, 7% fat), with a moderate-fat meal (600 kcal, 30% fat), or with a high-fat meal (870 kcal, 53% fat). The investigators collected serial samples to measure dolutegravir levels with each dose.
Taking dolutegravir with food raised plasma levels of dolutegravir and reduced its absorption, as reflected in a longer time to maximum concentration, which measured 2.1 hours when dolutegravir was taken fasting, 3.0 hours with a low-fat meal, 4.0 hours with a moderate-fat meal, and 5.0 hours with a high-fat meal.
Dolutegravir area under the concentration-time curve was 33% higher with a low-fat meal than fasting, 41% higher with a moderate-fat meal, and 66% higher with a high-fat meal. Trough (24-hour) concentrations of dolutegravir were 33% higher with a low-fat meal than fasting, 45% higher with a moderate-fat meal, and 73% higher with a high-fat meal. Compared with the fasting state, a low-, moderate-, or high-fat meal increased dolutegravir maximum concentrations by 46%, 52%, and 67%. Food did not affect dolutegravir elimination half-life.
No study participants experienced grade 2, 3, or 4 adverse events, and no one withdrew from the study because of an adverse event. The only drug-related adverse event was "feeling hot." The investigators recorded no clinically significant trends in clinical laboratory values, vital signs, or electrocardiograms.
The ViiV team concluded that the impact of food on dolutegravir levels is not clinically significant and that the integrase inhibitor can be taken without food or fat restrictions.
References
1. Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor, dolutegravir (S/GSK1349572). 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract P_12.
2. Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 151LB. http://www.natap.org/2011/CROI/croi_33.htm .
3. Arribas J, Lazzarin A, Raffi F, et al. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral naïve adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract THLBB20. http://www.natap.org/2010/IAS/IAS_54.htm.
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