Monitoring kidney function change with cobicistat

Cobicistat is a pharmacokinetic (PK) booster currently in phase 3 studies that unlike ritonavir has no direct antiretroviral activity. This Gilead booster might facilitate a wider range of coformulated boosted medicines: with elvitegravir and Quad (boosted elvitegravir plus Truvada) and with products developed by other companies (darunavir and atazanavir).

An early caution is that cobicistat produces significant reductions in estimated glomerular filtration rate (eGFR). These do not indicate clinically significant changes but will pose a problem for interpretation of routine monitoring tests where clinical changes in eGFR are a concern.

If average actual GFR (aGFR) is used to monitor cobicistat, determined by iohexol clearance (a probe drug excreted almost exclusively by glomerular filtration), no changes are observed.

At ICAAC, Gilead researchers presented results from a placebo controlled study in 36 HIV negative participants with normal renal function (eGFR >80 mL/min) and 18 HV negative participants with mildly impaired renal function (eGFR 50-79 mL/min).

Participants with normal function were randomised (12 per group) to one of three groups: 150 mg cobicistat + placebo; 100 mg ritonavir + placebo; or double placebo for 7 days, with both eGFR and aGFR measured at baseline, day 7 and day 14 (following a 7 day washout). All participants with reduced renal function took cobicistat for seven days with similar monitoring.

Independent of baseline eGFR, volunteers taking cobicistat experienced significant average reductions in eGFR by day seven which resolved seven days after discontinuation, with but showed no significant changes in aGFR (see Table 1). Similar changes were seen using either Cockcroft-Gault or MDRD to calculate eGFR. Participants taking ritonavir or placebo showed no significant changes in either measure.

The researchers interpret these findings to show that true GFR is not affected by cobicistat which affects proximal tubular secretion of creatinine.

While these results are reassuring in terms of clinical impact of cobicistat it is unclear how patients using other medications that affect eGFR would be managed in order not to misinterpret a genuine impact on real GFR.

German P et al. Effect of cobicistat on glomerular filtration rate (GFR) in subjects with normal and impaired renal function. 51st ICAAC, 17-20 September 2011, Chicago. Abstract H2-804.

Table 1: Changes in aGRF and aGFR (mL/min) in HIV negative people using cobicistat for 7 days
	aGFR	eGFR (Cockcroft-Gault)
Baseline eGFR	day 7	day 14	day 7	day 14
>80 mL/min	-2.7 (NS)	-2.5 (NS)	-9.9 (p<0.05)	+1.4 (NS)
50-79 mL/min	-3.6 (NS)	-5.8 (NS)	-11.9, p<0.05	-2.2 (NS)