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-) and maximum concentration of the drug in plasma (C max ) ranged from 16.7 g ⅐ h/ml (coefficient of variation [CV], 15%) and 1.5 g/ml (CV, 24%) at a 10-mg dose to 76.8 g ⅐ h/ml (CV, 19%) and 6.2 g/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval (C ) with a 50-mg dose was 1.6 g/ml, approximately 25-fold higher than the proteinadjusted 90% inhibitory concentration (0.064 g/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.The introduction of human immunodeficiency virus (HIV) integrase inhibitors has ushered in a potent new class of drugs for HIV-infected individuals. These agents act upon a key viral target and demonstrate activity in treatment-experienced patients (4, 7, 9). Importantly, their adverse event (AE) profile does not appear to have many of the dose-limiting side effects of other classes, such as central nervous system disturbances, hyperlipidemia, and insulin resistance. S/GSK1349572 is an investigational HIV integrase inhibitor that preferentially blocks the strand transfer step of integration of the viral genome into the host cell's DNA (6) and is designed to retain activity against raltegravir-and elvitegravirresistant HIV. The proposed mechanism of inhibition involves the drug molecule chelating to two Mg 2ϩ ions in the integrase DD(35)E catalytic active site. S/GSK1349572 was selected for clinical trials because nonclinical studies demonstrated a favorable safety profile, pharmacokinetics (PK) supporting once-daily dosing, and the potential fo...

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These data support the potential application of dual-therapy 744 LA and RPV LA for treatment of HIV-1 infection.

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 Ci). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

873140 demonstrated potent antiretroviral activity and was well tolerated. These results support further evaluation in Phase 2b/3 studies.

S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUC ss ) and the maximum, minimum, and average concentrations at steady state (C max,ss , C min,ss , and C avg,ss , respectively) increased in a dose-proportional manner over the 300-to 1,200-mg dose range. Steady-state clearance was dose independent. AUC ss /AUC 03ؕ decreased linearly with dose and correlated significantly with treatment-associated decreases in ␣ 1 -acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir C min,ss (0.280 g/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 g/ml), even after adjustment for protein binding. The median amprenavir C min,ss was also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 g/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C max . The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

GSK1265744 was well tolerated in healthy and HIV-1-infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load.