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S/GSK1265744  Audio icon

Other Names: GSK-1265744, GSK1265744, S-265744
Drug Class: Integrase Inhibitors
Molecular Formula: C19 H17 F2 N3 O5
Registry Number: 1051375-10-0 (CAS)
Company:
  • ViiV Healthcare
Phase of Development: IIb
Chemical Image:
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GSK-1265744
GSK-1265744
Molecular Weight: 405.3553
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, and ViiV Healthcare website3)

Pharmacology


Mechanism of Action: HIV-1 integrase strand transfer inhibitor. S/GSK1265744 prevents viral DNA integration into the host genome.4

: 21 to 50 days (long-acting parenteral [LAP] nanosuspension administered via intramuscular [IM] or subcutaneous [SC] injection); 40 hours (oral dosing).5

Metabolism/Elimination: S/GSK1265744 is primarily metabolized via glucuronidation.6  

Resistance: In vitro, S/GSK1265744 has exhibited activity against raltegravir-resistant isolates.7 

Exposure of MT-2 cells infected with HIV-1 IIIB to increasing concentrations of S/GSK1265744 for up to 112 days did not produce highly resistant mutants. Eight site-directed molecular clones containing single raltegravir mutations exhibited less than a 2 fold-change (FC) in S/GSK1265744 susceptibility (except Q148K/R, which demonstrated a 5.6/5.1 FC, respectively). Fifteen site-directed molecular clones containing 14 double-mutations exhibited less than a 12 FC. Cross-resistance to raltegravir and elvitegravir is limited.8


Dosing


S/GSK1265744 LAP can be administered via IM or SC injection.

Phase I (healthy adults):

  • S/GSK1265744 800-mg loading dose given at Month 1, followed by monthly maintenance doses (200 mg or 400 mg), with some participants receiving TMC278LA at Months 3-4; or S/GSK1265744 800 mg given alone once every 12 weeks.9
S/GSK1265744 can be administered once daily and orally.

Phase IIb (treatment-naive):

  • Induction phase: S/GSK1265744 10, 30, or 60 mg versus efavirenz 600 mg, each in combination with background NRTIs.
  • Maintenance phase: Those participants successfully completing the induction phase will continue their randomized dose of S/GSK1265744, but will discontinue background NRTIs and add rilpivirine 25 mg.10


Adverse Events


Single-dose S/GSK1265744 LAP formulation given via IM or SC injection has been generally safe and well tolerated, with reportedly good systemic safety in a Phase I study. The most common adverse event was mild-to-moderate, self-limited injection site reactions (ISR). ISR erythema and nodules were more frequent with SC dosing than with IM dosing. There were no drug-related serious or Grade 3-4 adverse events.5

Oral dosing (up to 50 mg single-dosing and up to 30 mg once daily repeat-dosing) was well tolerated in a Phase I/IIa study, with headache being the most common adverse event. There were no notable lab or ECG trends.11,12


Drug Interactions


S/GSK1265744 is neither an inducer nor an inhibitor of cytochrome P450 (CYP) or UGT enzymes. There are no apparent pharmacokinetic interactions between S/GSK1265744 and etravirine or between S/GSK1265744 and rilpivirine.6,13,14


References


1. United States National Library of Medicine. ChemIDplus Advanced.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.

3. ViiV Healthcare website. Our Pipeline. Accessed May 18, 2013.

4. Karmon SL, Markowitz M. Next-generation integrase inhibitors : where to after raltegravir? Drugs. 2013 Mar;73(3):213-28.

5. Spreen W, Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE040.

6. Ford SL, Gould E, Chen S, et al. Effects of etravirine on the pharmacokinetics of the integrase inhibitor S/GSK1265744. Antimicrob Agents Chemother. 2013 Jan;57(1):277-80.

7. Underwood M, St Clair M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1265744: a next generation integrase inhibitor (INI) with activity against raltegravir-resistant clinical isolates. Abstract presented at: 18th International AIDS Conference; July 18-23, 2010; Vienna, Austria. Abstract MOAA0103.

8. Yoshinaga T, Kobayashi M, Seki T, et al. Antiviral Characteristics Of S/GSK1265744, An HIV Integrase Inhibitor (INI) Dosed By Oral Or Long-acting Parenteral Injection. Abstract presented at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Abstract H-550.

9. ViiV Healthcare. A Randomized, Open Label Study to Investigate the Safety, Tolerability and Pharmacokinetics of Repeat Dose Administration of Long-Acting GSK1265744 and Long-Acting TMC278 Intramuscular and Subcutaneous Injections in Healthy Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 3, 2012. NLM Identifier: NCT 01593046. Last accessed May 18, 2013.

10. ViiV Healthcare. A Phase IIb, Dose Ranging Study of Oral GSK1265744 in Combination With Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic Suppression Followed by an Evaluation of Maintenance of Virologic Suppression When Oral GSK1265744 is Combined With Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2012. NLM Identifier: NCT01641809. Last accessed May 18, 2013.

11. Min S, DeJesus E, McCurdy L, et al. Pharmacokinetics (PK) and Safety in Healthy and HIV-Infected Subjects and Short-Term Antiviral Efficacy of S/GSK1265744, a Next Generation Once Daily HIV Integrase Inhibitor. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12–15, 2009; San Francisco, CA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2009. Accessed May 18, 2013.

12. Min S, DeJesus E, McCurdy L, et al. Pharmacokinetics (PK) and Safety in Healthy and HIV-Infected Subjects and Short-Term Antiviral Efficacy of S/GSK1265744, a Next Generation Once Daily HIV Integrase Inhibitor. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12–15, 2009; San Francisco, CA. Abstract H-1228.

13. Ford SL, Chen S, Gould E, et al. Etravirine has no effect on the pharmacokinetics of S/GSK1265744, a novel HIV Integrase inhibitor. Abstract presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract P_15.

14. Ford SL, Gould E, Chen S, et al. Lack of Pharmacokinetic (PK) Interaction between Rilpivirine and the Integrase Inhibitors Dolutegravir and S/GSK1265744. Abstract presented at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Abstract A-1249.


Last Reviewed: May 23, 2013

Last Updated: May 23, 2013