icon-folder.gif   Conference Reports for NATAP  
  5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
July 19th-22nd 2009
Capetown, South Africa
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Pharmacokinetics (PK) and Safety in Healthy Subjects of S/GSK1349572, a Next Generation, Once-Daily HIV Integrase Inhibitor (INI)
  Reported by Jules Levin
5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, July 19-22, 2009

Sherene Min, Ivy Song, Julie Borland, Shuguang Chen,
Yu Lou, Tamio Fujiwara, Stephen Piscitelli
GlaxoSmithKline, RTP, NC, USA, Shionogi & Co., Ltd., Osaka, Japan


- S/GSK1349572 was generally well tolerated in healthy subjects
- S/GSK1349572 can be given with or without food
- S/GSK1349572 does not affect CYP3A
- S/GSK1349572 demonstrates predictable and consistent pharmacokinetics with low PK variability
- The PK profile supports low dose, once daily dosing and will achieve target therapeutic concentrations without the need for a PK booster


Background: S/GSK1349572 is an HIV integrase strand transfer inhibitor that demonstrates potent in vitro anti-HIV activity and a favorable preclinical profile.

Methods: Randomized, double-blind, placebo-controlled first in human single-dose (SD) and multiple-dose (MD), dose escalation studies were conducted. In the SD study, 2 cohorts of 10 subjects (8 active, 2 placebo) received suspension doses of 2, 5, 10, 25, 50 and 100 mg in an alternating panel design. In the MD study, 3 cohorts of 10-12 subjects (8 or 10 active, 2 placebo) received suspension doses of 10, 25 and 50mg once daily for 10 days, and a CYP3A substrate, midazolam, was given on Day -1 alone and on Day 10 with the 25 mg dose. An additional 12 subjects received 20mg suspension and two 10mg tablets with and without a 30% fat meal in a crossover design. Laboratory testing, vital signs, ECGs and PK sampling were performed at regular intervals.

Results: Most adverse events (AE) were mild; headache was the most common AE. No laboratory or ECG trends were noted. PK was dose proportional and time-invariant over the dosage range studied. Median elimination half-life was 15 hours. Steady state geometric mean (CV%) AUC(0-24) and Cmax ranged from 16.7 (15) µg*h/mL and 1.5 (24) µg/mL at 10 mg once daily to 76.8 (19) µg*h/mL and 6.2 (15) µg/mL at 50mg once daily, respectively. The geometric mean steady-state C24 at 50mg was 1.5 µg/mL, -23-fold higher than the in vitro protein-adjusted IC90. S/GSK1349572 had no impact on midazolam PK. The tablet demonstrated relative bioavailability of 70% compared to suspension. Food had no impact on tablet exposure.

Conclusions: S/GSK1349572 was well tolerated in healthy subjects. The PK profile indicates once daily low doses of S/GSK1349572 will achieve target therapeutic concentrations. S/GSK1349572 is being evaluated in HIV-infected patients.


Next generation integrase inhibitors should provide real advances for patients including:

A unique resistance profile allowing treatment of raltegravir and elvitegravir resistant virus

QD dosing without the need for concomitant pharmacokinetic boosters

S/GSK1349572 was engineered to deliver these attributes










Treatment: 10mg = 10mg S/GSK1349572 suspension once daily x 10 days, 25mg = 25mg S/GSK1349572 suspension once daily x 9 days, 50mg = 50mg S/GSK1349572 suspension once daily x 10 days, MDZ = 3mg MDZ single dose, 25mg + MDZ = 25mg S/GSK1349572 suspension + 3mg MDZ once daily x 1 day