Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function.
OBJECTIVE
This study evaluated the effect of cobicistat (COBI) on glomerular filtration rate in subjects with normal renal function (RF) or with mild/moderate renal impairment, by comparing creatinine clearance [estimated glomerular filtration rate (eGFR)] with actual GFR (aGFR) using iohexol, a probe drug excreted by glomerular filtration. COBI is a potent CYP3A inhibitor (pharmacoenhancer) currently in phase 3 testing with elvitegravir, atazanavir, and darunavir.


METHODS
Normal RF subjects received COBI 150 mg QD, ritonavir (RTV) 100 mg QD, or placebo for 7 days; subjects with mild/moderate renal impairment received COBI 150 mg QD. The eGFR and aGFR were measured on days 0, 7, and 14 and within-subject changes calculated relative to day 0. COBI and RTV pharmacokinetics were analyzed on day 7.


RESULTS
All 36 subjects in cohort 1 and 17 of 18 subjects in cohort 2 completed all study treatments. Study treatments were well tolerated. Small increases in serum creatinine with corresponding mean decreases in eGFR (∼10 mL/min or mL/min per 1.73 m) were observed on day 7 relative to day 0 in subjects receiving COBI (P < 0.05). The decreases were reversible on COBI discontinuation; mean eGFR values returned to baseline on day 14 (P > 0.05). No statistically significant changes in aGFR on days 7 or 14 relative to day 0 were seen with COBI (P > 0.05). No statistically significant decreases in aGFR or eGFR were observed with RTV or placebo.


CONCLUSIONS
COBI affects eGFR but not the actual GFR. The time to onset, magnitude, and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of drug transporters.
Gilead Sciences, Inc, Foster City, CA 94404, USA. polina.german@gilead.com
Polina
P
German
Hui C
HC
Liu
Javier
J
Szwarcberg
Mischa
M
Hepner
Jessica
J
Andrews
Brian P
BP
Kearney
Anita
A
Mathias
D000328:Adult; D002219:Carbamates / Q000008:administration & dosage*; D000069547:Cobicistat; D015331:Cohort Studies; D003404:Creatinine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate; D010919:Placebos / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage*
D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D010919:Placebos; D013844:Thiazoles; D003404:Creatinine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D000069547:Cobicistat