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...

Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.

Aim Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr) was evaluated in 34 healthy volunteers. Methods Subjects received DTG 50 mg (once daily or twice daily) or placebo for 14 days. GFR was measured by iohexol plasma clearance, ERPF was assessed by para‐aminohippurate plasma clearance and CLcr was measured by 24 h urine collection. Results All treatments were generally well tolerated. A modest decrease (10–14%) in CLcr was observed, consistent with clinical study observations. DTG 50 mg once daily and twice daily had no significant effect on GFR or ERPF compared with placebo over 14 days in healthy subjects. Conclusions These findings support in vitro data that DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine.