| Reference | 1. AIDS. 2010 Nov 13;24(17):2753-5. doi: 10.1097/QAD.0b013e32833f9e36.<br />
In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572.<br />
Charpentier C(1), Larrouy L, Collin G, Damond F, Matheron S, Chêne G, Nie T, Schinazi R, Brun-Vézinet F, Descamps D; French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).<br />
Author information:<br />
(1)Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Université Paris-Diderot, France.<br />
In this study of nine clinical isolates obtained from integrase inhibitor-naïve HIV-2-infected patients, the median EC₅₀ value for the new integrase inhibitor S/GSK1349572 was 0.8 nM (range 0.2-1.4), and is similar to HIV-1 reference strains. We found a seven-, 13- and 18-fold increase in EC₅₀ values to S/GSK1349572 for the HIV-2 double (T97A + Y143C; G140S + Q148R) and triple (G140T + Q148R + N155H) mutants, respectively, obtained from two raltegravir-experienced patients.<br />
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2. J Acquir Immune Defic Syndr. 2010 Nov;55(3):365-7. doi: 10.1097/QAI.0b013e3181e67909.<br />
Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects.<br />
Song I(1), Min SS, Borland J, Lou Y, Chen S, Ishibashi T, Wajima T, Piscitelli SC.<br />
Author information:<br />
(1)GlaxoSmithKline, Research Triangle Park, NC 27709, USA.<br />
BACKGROUND: The potential for a drug interaction between S/GSK1349572 and tenofovir disoproxil fumarate (TDF) was evaluated in an open-label, repeat dose, 3-period, drug-drug interaction study in healthy subjects.<br />
METHODS: S/GSK1349572 was administered at 50 mg once daily for 5 days (period 1) followed by a 6-day washout period. TDF 300 mg once daily was then administered for 7 days (period 2). The combination of S/GSK1349572 and TDF was then coadministered for 5 days (period 3). Pharmacokinetic parameters were determined and compared between periods.<br />
RESULTS: Fifteen subjects completed all periods and follow-up. S/GSK1349572 and TDF were generally well tolerated with few adverse events reported. No clinically significant trends in post-dose laboratory abnormalities, vital signs, or electrocardiogram values were noted. Pharmacokinetic parameters of S/GSK1349572 and tenofovir during combination therapy were similar to those when given alone, demonstrating no significant drug interaction. S/GSK1349572 geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), Cmax, and Cτ were 1.01 (0.908, 1.11), 0.969 (0.867, 1.08), and 0.920 (0.816, 1.04), respectively. Tenofovir geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), Cmax, and Cτ were 1.12 (1.01, 1.24), 1.09 (0.974, 1.23), and 1.19 (1.04, 1.35), respectively.<br />
CONCLUSION: S/GSK1349572 and TDF can be coadministered without dose adjustment.<br />
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3. Antimicrob Agents Chemother. 2010 Jan;54(1):254-8. doi: 10.1128/AAC.00842-09. Epub 2009 Nov 2.<br />
Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers.<br />
Min S(1), Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC.<br />
Author information:<br />
(1)Infectious Diseases MDC, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.<br />
S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV activity, an in vitro resistance profile different from those of other integrase inhibitors, and favorable preclinical safety and pharmacokinetics (PK). Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 100 mg in an alternating panel design. In the multiple-dose study, three cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy with midazolam was conducted with the 25-mg dose. Laboratory testing, vital signs, electrocardiograms (ECGs), and PK sampling were performed at regular intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, with a few moderate AEs reported. Headache was the most common AE. No clinically significant laboratory trends or ECG changes were noted. PK was linear over the dosage range studied. The steady-state geometric mean area under the concentration-time curve over a dosing interval (AUC(0-tau)) and maximum concentration of the drug in plasma (C(max)) ranged from 16.7 microg.h/ml (coefficient of variation [CV], 15%) and 1.5 microg/ml (CV, 24%) at a 10-mg dose to 76.8 microg.h/ml (CV, 19%) and 6.2 microg/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval (C(tau)) with a 50-mg dose was 1.6 microg/ml, approximately 25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 microg/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations.<br />
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