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Kidney Function Change With Cobicistat Calculated in HIV-Negative Volunteers
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Estimated glomerular filtration rate (eGFR) dropped significantly in healthy volunteers with normal kidney function or mild to moderate impairment during 7 days of dosing with cobicistat, the antiretroviral boosting agent [1]. Average eGFR returned to normal in all volunteers 7 days after cobicistat stopped. Average actual GFR (aGFR), determined by iohexol clearance, did not change significantly in volunteers with or without mild to moderate kidney impairment through 7 days of dosing.
Cobicistat, a boosting agent with no anti-HIV activity, is being tested in combination with the integrase inhibitor elvitegravir and the protease inhibitor atazanavir in phase 3 trials. Phase 1 and 2 study participants had small jumps in creatinine and drops in eGFR (estimated by the Cockcroft-Gault formula) when taking cobicistat, and those declines reversed after people stopped cobicistat. Even a moderate impact of cobicistat on kidney function could be important in people taking other drugs, such as tenofovir, that affect renal function. Cobicistat is part of an investigational 4-in-1 antiretroviral combining tenofovir, emtricitabine, and elvitegravir.
Researchers at Gilead Sciences, developer of cobicistat and elvitegravir, planned this study of HIV-negative volunteers with normal or impaired kidney function to calculate eGFR and aGFR after 7 days of cobicistat dosing and at day 14, a week after cobicistat stopped. They calculated aGFR by measuring clearance of iohexol, a probe drug excreted almost exclusively by glomerular filtration. The researchers recruited two groups of volunteers: 36 people with normal kidney function (eGFR at or above 80 mL/min) and 18 people with mild to moderately impaired kidney function (eGFR 50 to 79 mL/min).
Everyone in the impaired-function group took 150 mg of cobicistat daily for 7 days. Volunteers with normal kidney function took (1) that dose of cobicistat plus ritonavir placebo for 7 days, (2) 100 mg of ritonavir daily plus cobicistat placebo for 7 days, or (3) cobicistat and ritonavir placebo for 7 days (12 volunteers per group). The Gilead team determined eGFR and aGFR on days 0, 7, and 14.
In volunteers with normal kidney function, aGFR fell by an average 2.7 mL/min by day 7 and by an average 2.5 mL/min by day 14, both nonsignificant changes. Neither aGFR nor eGFR changed significantly by day 7 or 14 in volunteers with normal kidney function taking ritonavir or placebo.
In volunteers with normal kidney function taking cobicistat, average Cockroft-Gault-determined eGFR fell significantly by day 7 (-9.9 mL/min, P < 0.05), and by day 14 (a week after cobicistat stopped) average eGFR change was no longer statistically significant (+1.4 mL/min). Respective eGFR changes by the MDRD method were -9.90 mL/min (P < 0.05) and +1.10 mL/min.
In cobicistat-treated volunteers with mild to moderate kidney impairment, aGFR did not change significantly by day 7 (-3.6 mL/min) or day 14 (-5.8 mL/min). In this group eGFR fell significantly after 7 days of cobicistat dosing by the Cockroft-Gault method (-11.9 mL/min, P < 0.05) and by the MDRD method (-13.9 mL/min, P < 0.05). But by day 14 (7 days after cobicistat stopped), change in average eGFR was no longer statistically significant by Cockroft-Gault (-2.2 mL/min) or MDRD (-2.6 mL/min).
The Gilead team concluded that cobicistat "does not affect true GFR" as determined by iohexol clearance. They proposed that "alteration of eGFR but not in aGFR suggests cobicistat affects proximal tubular secretion of creatinine."
In a separate study, Gilead investigators used in vitro systems to assess the effects of cobicistat and other drugs that affect eGFR on proximal renal tubular cell transporters that may play a role in tubular creatinine secretion [2]. Besides cobicistat, the drugs were cimetidine, trimethoprim, dolutegravir, and ritonavir. The experiments determined whether these agents inhibited an array of renal transporters (OCT2, MATE1, MATE2-K, OCTN1, BCRP, Pgp, and MRP2) in transfected cells lines.
Most tested drugs, including cobicistat, inhibited multidrug and toxin extrusion protein 1 (MATE1) most strongly. The researchers proposed that cobicistat "appears to affect eGFR by inhibiting MATE1-mediated efflux of creatinine." Ritonavir, trimethoprim, and cimetidine appeared to affect eGFR by a similar mechanism in these experiments.
References
1. German P, Liu C, Warren D, et al. Effect of cobicistat on glomerular filtration rate (GFR) in subjects with normal and impaired renal function. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H2-804.
2. Lepist EI, Murray BP, Tong L, Roy A, Bannister R, Ray AS. Effect of cobicistat and ritonavir on proximal renal tubular cell uptake and efflux transporters. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract A1-1724.
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