A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para‐aminohippurate clearance in healthy subjects

Aim Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr) was evaluated in 34 healthy...

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Published in:British journal of clinical pharmacology 2013-04, Vol.75 (4), p.990-996
Main Authors: Koteff, Justin, Borland, Julie, Chen, Shuguang, Song, Ivy, Peppercorn, Amanda, Koshiba, Takaaki, Cannon, Courtney, Muster, Heather, Piscitelli, Stephen C.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Clinical Trials
Creatinine - urine
creatinine clearance
dolutegravir (DTG
Female
glomerular filtration rate
Glomerular Filtration Rate - drug effects
Heterocyclic Compounds, 3-Ring - adverse effects
Heterocyclic Compounds, 3-Ring - pharmacology
HIV integrase
HIV Integrase Inhibitors - adverse effects
HIV Integrase Inhibitors - pharmacology
Humans
iohexol
Iohexol - pharmacokinetics
Male
Middle Aged
Oxazines
p-Aminohippuric Acid - pharmacokinetics
Piperazines
Pyridones
Renal Plasma Flow - drug effects
S/GSK1349572
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Summary:Aim Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr) was evaluated in 34 healthy volunteers. Methods Subjects received DTG 50 mg (once daily or twice daily) or placebo for 14 days. GFR was measured by iohexol plasma clearance, ERPF was assessed by para‐aminohippurate plasma clearance and CLcr was measured by 24 h urine collection. Results All treatments were generally well tolerated. A modest decrease (10–14%) in CLcr was observed, consistent with clinical study observations. DTG 50 mg once daily and twice daily had no significant effect on GFR or ERPF compared with placebo over 14 days in healthy subjects. Conclusions These findings support in vitro data that DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine.
ISSN:0306-5251
1365-2125
1365-2125
DOI:10.1111/j.1365-2125.2012.04440.x