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. .
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
38
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.
GSK Investigational Site
Minneapolis, Minnesota, United States
Glomerular Filtration Rate (GFR) as measured by iohexol plasma clearance at days -1, 7 and 14
Time frame: 14 days
Serum creatinine, creatinine clearance (CrCL) as measured by 24-hour urine collection, and extra-glomerular creatinine excretion (EGCE) at days -1, 7, 14 and follow-up
Time frame: 24 days
Serum concentrations of Cystatin-C, 24-hour urinary excretions of albumin, total protein, beta2-microblobulin, N-acetyl-beta-d-glucosaminidase (NAG) and retinol binding protein at days -1, 7, 14 and at follow-up
Time frame: 24 days
Effective renal plasma flow (ERPF) as measured by plasma clearance of Para Aminohippurate (PAH) at days -1, 7 and 14
Time frame: 14 days
Safety and tolerability parameters, including adverse event, concurrent medication, clinical laboratory and vital signs assessments.
Time frame: 24 days
Day 14 GSK1349572 PK parameters including area under the concentration curve (AUC)(0-tau), AUC(0-24), concentration (C)max, C0, and Ctau.
Time frame: day 14
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