title: Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers.
abstract: 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.
authors.affiliation: Infectious Diseases MDC, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Sherene
authors.initials: S
authors.lastname: Min
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006261:Headache / Q000139:chemically induced; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012894:Sleep Stages / Q000187:drug effects; D055815:Young Adult; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir