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Dolutegravir & Creatinine Clearance
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Small Drop in Creatinine Clearance With Dolutegravir in Healthy Volunteers
51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Dolutegravir, an investigational integrase inhibitor, modestly decreased creatinine clearance in a placebo-controlled trial involving healthy HIV-negative volunteers [1]. The investigators believe this change involves a benign mechanism that will not pose problems for people taking dolutegravir. Compared with placebo, dolutegravir had no impact on glomerular filtration rate or renal plasma flow in this study.
Earlier clinical trials found small increases in serum creatinine in people taking dolutegravir [2], a once-daily unboosted integrase inhibitor now in phase 3 trials in antiretroviral-naive and integrase inhibitor-resistant people. Creatinine rose 6.4 to 11.9 umol/L at study week 1, remained stable to week 20, then fell through week 48 [3]. Researchers at ViiV Healthcare, dolutegravir's developer, attribute this reversible jump in creatinine to inhibition of organic cation transporter 2 (OCT2), which mediates tubular secretion of creatinine.
This open-label, placebo-controlled trial involved 34 healthy volunteers randomized to 50 mg of dolutegravir once or twice daily or to placebo for 14 days. (In phase 3 trials the dose of dolutegravir is 50 mg once daily.) Volunteers also received iohexol and PAH infusions 1 day before starting the study drug (day -1) and on treatment days 7 and 14.
On day 14 ViiV investigators estimated glomerular filtration rate by iohexol plasma clearance, renal plasma flow by para-aminohippurate (PAH) clearance, and creatinine clearance by 24-hour urine collection. The researchers adjusted all these values for body surface area. The ViiV team believes iohexol clearance is a better indicator of glomerular filtration than serum creatinine because iohexol is not secreted or reabsorbed in the renal tubule.
Of the 38 people who enrolled in the trial, 28 were men, and 29 white. Their age averaged 32 years (standard deviation 11.6). Three people withdrew consent before dolutegravir dosing and 1 person withdrew because of nausea and loss of appetite. The other 34 volunteers completed all study assessments.
The day 14/day -1 ratio for iohexol clearance with dolutegravir showed virtually no impact on glomerular filtration rate with once-daily dolutegravir versus placebo (0.993, 90% confidence interval [CI] 0.915 to 1.08) or with twice-daily dolutegravir versus placebo (1.05, 90% CI 0.963 to 1.14).
Likewise, the day 14/day -1 ratio for PAH clearance with dolutegravir showed no change in renal plasma flow with once-daily dolutegravir versus placebo (1.03, 90%CI 0.921 to 1.15) or with twice-daily dolutegravir versus placebo (0.969, 90% CI 0.886 to 1.08).
Once-daily dolutegravir decreased creatinine clearance by 10% when calculated as day 14/day -1 ratio (0.900, 90% CI 0.808 to 1.00), while twice-daily dolutegravir lowered creatinine clearance by 14% (0.861, 90% CI 0.772 to 0.960).
No one taking once-daily dolutegravir had drug-related adverse events. Three drug-related adverse events in the twice-daily dolutegravir group included decreased appetite in 2 people. The study disclosed no clinically significant changes in mean or median hematology or clinical chemistry values.
The investigators concluded that dolutegravir decreased creatinine clearance by 10% to 14% "but had no effect on placebo-corrected iohexol and PAH clearance." Creatinine increases were comparable to those in phase 2b trials. The researchers believe these findings suggest that "reversible increases in creatinine observed in clinical studies are due to the nonpathologic inhibition of OCT2 in the proximal renal tubules, and represent a benign effect on renal handling of creatinine."
References
1. Koteff J, Borland J, Chen S, et al. An open label, placebo-controlled study to evaluate the effect of dolutegravir (DTG, S/GSK1349572) on iohexol and para-aminohippurate clearance in healthy subjects. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract A1-1728.
2. Van Lunzen J, Maggiolo F, Phung B, et al. Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naive adults: 48 week results from SPRING-1 (ING112276). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract TUAB0102. http://www.natap.org/2011/IAS/IAS_05.htm.
3. Min S, Carrod A, Curtis L, et al. Safety profile of dolutegravir (DTG, S/GSK1349572), in combination with other antiretrovirals in antiretroviral (ART)-naive and ART-experienced adults from two phase IIb studies. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract TUPE238. http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200742790.
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