A Phase 1, Open Label, Placebo-Controlled Study to Evaluate the Effect of GSK1349572 on Iohexol and Para-Aminohippurate Clearance in Healthy Subjects
Condition: Infections, Human Immunodeficiency Virus and Tuberculosis
MeSH terms: Tuberculosis; Acquired Immunodeficiency Syndrome; HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The current study is designed to confirm the mechanism behind the increase in serum
      creatinine observed during GSK1349572 therapy; specifically, the study will determine whether
      GSK1349572 has any effect on glomerular filtration rate (GFR) or effective renal plasma flow.
      Absent such effects, one may conclude that the small increases in serum creatinine observed
      are due to the inhibition of the tubular secretion of creatinine via organic cation
      transporter 2 (OCT2) consistent with in vitro data. .
    

Detailed description: 
      GSK1349572 is an integrase inhibitor being developed for the treatment of human
      immunodeficiency virus (HIV)-1 infection by GlaxoSmithKline (GSK) on behalf of Shionogi-ViiV
      Healthcare LLC. In healthy subjects and in dose-ranging clinical trials of GSK1349572,
      subjects showed a small, reversible increase in serum creatinine concentrations as compared
      to the control groups; this occurred early during study drug administration and did not
      progress over time. In vitro data demonstrate that GSK1349572 inhibits the organic cation
      transporter (OCT2), which mediates the tubular secretion of creatinine; drugs such as
      cimetidine with similar effects on OCT2 lead to a nonpathological increase in creatinine with
      no effect on glomerular filtration rate (GFR). The current study is designed to confirm the
      mechanism behind the increase in serum creatinine observed during GSK1349572 therapy;
      specifically, the study will determine whether GSK1349572 has any effect on GFR or effective
      renal plasma flow. Absent such effects, one may conclude that the small increases in serum
      creatinine observed are due to the inhibition of the tubular secretion of creatinine via
      OCT2.

      Subjects will be given GSK1349572 50mg once daily, 50mg twice daily or placebo once daily for
      14 days. Changes in the subject's GFR will be measured through administration of iohexol and
      effective renal plasma flow will be measured using Para-Aminohippurate (PAH) on days -1, 7
      and 14. Changes in serum creatinine and other renal biomarkers will be evaluated at baseline
      and at various time points throughout the study.
    

Intervention name(s): GSK1349572; Placebo; Iohexol Injection; Para-aminohippurate infusion
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): GSK1349572 is an experimental drug in the integrase inhibitor class of drugs to treat human immunodeficiency virus (HIV); Placebo is a tablet with no drug in it.; Iohexol is an FDA approved radiologic contrast medium; Para-aminohippurate is an agent to measure effective renal plasma flow.
Other intervention name(s): OMNIPAQUE
Intervention MeSH terms: Dolutegravir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GSK1349572; para-aminohippurate; iohexol