Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Abstract

Healthy subjects received dolutegravir at 50 mg in a single-dose crossover study while they were in the fasted state or with low-, moderate-, or high-fat meals. Food increased dolutegravir exposure and reduced the rate of absorption. The area under the concentration-time curve from 0 h to infinity (AUC 0 -ؕ ) increased by 33%, 41%, and 66% when administered with low-, moderate-, or high-fat meals, respectively, compared with fasting. This increase in dolutegravir exposure is not anticipated to impact clinical safety, and therefore dolutegravir can be taken with or without food and without regard to fat content. D olutegravir (DTG; S/GSK1349572) is an integrase inhibitor for the treatment of HIV infection, does not require boosting with ritonavir, and possesses activity against raltegravir-resistant strains (3,4). DTG is currently in phase III clinical development at a dose of 50 mg once daily in treatment-naive and integrase-naïve treatment-experienced subjects and at 50 mg twice daily in subjects with resistance to raltegravir or elvitegravir. The pharmacokinetic (PK) profile of DTG is characterized by achievement of high plasma drug exposures, a half-life of approximately 15 h, low to moderate intersubject variability, and a well-described PK/ pharmacodynamic relationship (5, 6). The ability to administer antiretroviral medications with or without food is an important aspect of dosing convenience. Drugs that do not have food restrictions are preferred by patients and allow them to take their medications without regard to timing or content of meals. The objective of this study was to evaluate the effect of meals with various fat and calorie contents on the PK of DTG.(These data were presented in part at the 12th International Workshop on the Clinical Pharmacology of HIV Therapy, Coral Gables, FL, April 2011.) This was a two-part, single-center, randomized, open-label, crossover study of healthy adult male and female subjects. The sample size was 24 subjects in part 1 and 18 subjects in part 2. In part 1, 24 subjects received DTG at 50 mg as a single dose after an overnight fast of at least 6 h. Eighteen of these subjects were enrolled into part 2 and were randomized to receive a single 50-mg dose on three separate occasions with a low-fat (300 kcal, 7% fat), moderate-fat (600 kcal, 30% fat), or high-fat (870 kcal, 53% fat) meal. To avoid selection bias, the first 18 subjects who were enrolled in part 1 who still met all eligibility criteria continued to part 2. Serial blood samples for PK analysis were collected predosing and 1, 2,3,4,5,6,8, 12, 24, and 48 h postdosing. There was a washout period of 7 days between doses. Safety evaluations included physical exam, vital signs, electrocardiograms, a full laboratory panel, and daily monitoring for adverse events (AEs). Subjects had a follow-up visit within 7 to 14 days after the last dose.Subjects were judged to be healthy by physical exam, medical history, and laboratory testing. Exclusion criteria included a positive HIV or hepatitis C virus antibody result, a...

Metabolism, Excretion, and Mass Balance of the HIV-1 Integrase Inhibitor Dolutegravir in Humans

“…Thus, absorption of dolutegravir is expected to be higher than that reflected by fecal elimination, and the total systemic burden of absorbed material would be approximately 70% to 80%. Food was noted to modestly increase systemic exposure to dolutegravir, but the effect is not clinically significant, and dolutegravir can be taken without regard to meals (11,18). Therefore, the results from this study are applicable to the nonfasted or fasted state, as food is not expected to alter the metabolic profile of dolutegravir.…”

Divalent Metals and pH Alter Raltegravir Disposition In Vitro

“…Elvitegravir and dolutegravir exposure has been shown to be reduced when these drugs are taken with antacids containing magnesium and aluminum, with the reduction being less marked when the drug is taken 2 h before the antacid (19,21). In healthy subjects, elvitegravir and dolutegravir absorption has also been shown to be influenced by food according to fat content (26,9), and it is recommended that elvitegravir be taken with food (20). Interestingly, dolutegravir exposure has also been shown to be moderately reduced when the drug is taken with a multivitamin containing magnesium, calcium, iron, zinc, and copper (19).…”

Use of Integrase Inhibitors in HIV-Infected Children and Adolescents

“…As a result, dolutegravir should be administered twice daily in patients receiving either efavirenz or nevirapine [84]. Patients receiving etravirine and dolutegravir experienced significant reductions in the AUC 24 , C max , and C min values for dolutegravir [85]. However, concomitant use of ritonavir with lopinavir, atazanavir, or darunavir in these patients prevented decreases in the AUC 24 and C max and increased dolutegravir trough concentrations by up to 28 % when co-administered with etravirine [85].…”

“…Patients receiving etravirine and dolutegravir experienced significant reductions in the AUC 24 , C max , and C min values for dolutegravir [85]. However, concomitant use of ritonavir with lopinavir, atazanavir, or darunavir in these patients prevented decreases in the AUC 24 and C max and increased dolutegravir trough concentrations by up to 28 % when co-administered with etravirine [85]. Protease inhibitors may either inhibit the metabolic pathways for dolutegravir (e.g.…”

“…No dose adjustments are necessary with many protease inhibitors, though patients receiving tipranavir/ritonavir or fosamprenavir/ritonavir will require twice-daily dosing of dolutegravir due to significant reductions in the AUC s , C max , and C s when these medications are co-administered [81,84]. Dolutegravir may be taken without any concern of interaction with food; however, a high-fat meal will increase the absorption of dolutegravir [85]. Dolutegravir administration must be 6 h after or 2 h prior to use of antacids given the potential for chelation with metal cations, such as magnesium, aluminum, or calcium, leading to reduced absorption [86].…”