S/GSK1349572, a new integrase inhibitor for the treatment of HIV: promises and challenges

Lenz, J.; Rockstroh, Jürgen K.

doi:10.1517/13543784.2011.562189

Cited by 21 publications

(17 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Song

Borland

Chen

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Song

Borland

Chen

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Integrase inhibitors (INIs) are mainly metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1. These INIs are neither inducers nor inhibitors of CYP3A4 (4,5). Therefore, they presumably do not interact with CNIs (2).…”

Section: Discussionmentioning

confidence: 99%

“…Its global phase III trials are currently in progress. During a phase II trial with HAART-naïve subjects, its non-inferior efficacy was demonstrated to be not inferior to that of efavirenz (NNRTI) (Sustiva, Bristol-Myers Squibb Pharma Company, New York, USA) (5). In vitro studies have raised the curious possibility that DTG could have the potential of a higher genetic barrier to resistance than RAL, in the setting of INI-naïve patients (9) (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, though, integrase inhibitors (INIs) have emerged. They are novel, potent anti-HIV drugs characterized by a distinct metabolic pathway; they include raltegravir (RAL, Isentress, Merck & Co., Inc., New Jersey, USA) and dolutegravir (DTG, S/GSK1349572, ViiV Healthcare/Shionogi, Middlesex,UK/Osaka, Japan) (4,5). Currently, their implications in the setting of Tx for HIV positive patients are being actively discussed.…”

mentioning

confidence: 99%

See 1 more Smart Citation