Antiviral activity in vitro with S/GSK1265744
Polly Clayden, HIV i-Base
The development of long acting formulations of antiretrovirals arouses great interest – and frequently tops the wish lists of treaters of adolescents.
Cell culture data from S/GSK 1265744, the investigational integrase inhibitor, shown at ICAAC 2012, suggests it has a favourable resistance profile. 
S/GSK1265744 is in development both as a long acting parental formulation and the back up oral formulation to dolutegravir. Phase 1 data shown at IAS 2012 using 200 mg/mL nanosuspension administered by intramuscular – dosed at 100 to 800 mg – or subcutaneous abdominal injection – at 100 mg to 400 mg – in HIV negative people produced an apparent plasma half-life of 25-50 days and supports parenteral once monthly dosing. 
Results presented at ICAAC were from a study accessing resistance in cell culture, in which HIV-1 IIIB was passaged in MT-2 cells with increasing concentrations of S/GSK1265744 and the integrase gene was sequenced. Fold changes were calculated as a ratio of IC50 against wild type virus.
The investigators reported S/GSK1265744 IC50 of 0.22 nM in human peripheral blood mononuclear cells (PBMC). IC50s for dolutegravir, raltegravir and elvitegravir were respectively 0.51, 2.0 and 2.0 nM. The fold potency shift for 100% human serum was 408 for S/GSK1265744, and 75, 4.7 and 22 for dolutegravir, raltegravir and elvitegravir. The protein adjusted IC50 estimate for S/GSK1265744 was 102 nM compared to 38, 5.6 and 20 nM for dolutegravir, raltegravir and elvitegravir respectively.
Exposure of MT-2 cells infected with HIV-1 IIIB to S/GSK1265744 for up to 112 days did not produce highly resistant mutants. The maximum resistance was 8.4 fold. Raltegravir/elvitegravir resistant signature mutation site-directed molecular clones had less than 2-fold change in susceptibility to S/GSK1265744, except for Q148K/R, which had 5.6/5.1 fold change, respectively. Fold changes of 14 double mutants among 15 site directed molecular clones were less than 12.
A poster at ICAAC showed results from a phase 1, open-label, two-cohort, single sequence crossover study, looking at the effects of oral co-administration of rilpivirine with S/GSK1265744 (also dolutegravir). 
HIV negative subjects received S/GSK1265744 30 mg once daily for 12 days followed by a washout, rilpivirine 25 mg once daily for 12 days, and rilpivirine 25 mg plus S/GSK1265744 30 mg for 12 days, taken following a moderate fat meal. Serial PK sampling was performed on the last day of each dosing period.
This evaluation found similar S/GSK1265744 and rilpivirine PK parameters when administered separately or together. Bioequivalence criteria were met for all parameters except S/GSK1265744 decreased rilpivirine Cmin by 8%, which is not considered clinically relevant. This lack of interaction is promising for co-administration in long-acting depot injection regimens.
- Yoshinaga T et al. Antiviral characteristics of S/GSK1265744, an HIV integrase inhibitor (INI) dosed by oral or long-acting parenteral Injection. 52nd ICAAC, San Francisco, 9-12 September 2012. Oral abstract H-550.
- Spreen W et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. 19th International AIDS Conference 22-27 July 2012. Washington, DC. Poster abstract TUPE040.
- Ford SL et al. Lack of pharmacokinetic (PK) interaction between rilpivirine and the integrase inhibitors dolutegravir and S/GSK1265744. 52nd ICAAC, San Francisco, 9-12 September 2012. Poster abstract A-1249.