Dolutegravir has several characteristics that, in theory, suggest it will not be significantly removed by dialysis: It has a large apparent volume of distribution (17.4 L) and is highly protein bound (98.9%). A small study of 5 HIV-infected patients with end-stage renal disease undergoing conventional hemodialysis or hemodiafiltration was presented at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) and supports this hypothesis. Participants added 50 mg of dolutegravir every morning to their existing ART regimen. Dolutegravir predialysis and postdialysis concentrations were measured on day 5. An extraction ratio was calculated to estimate the proportion of dolutegravir removed, and a correction factor was applied to account for protein binding. Median dolutegravir concentration at the beginning of the dialysis session was 1.52 mg/L (range = 0.48-2.90 mg/L) while median dolutegravir concentration at the end of the dialysis session was 2.18 mg/L (range = 0.86-2.77 mg/L). Increased postdialysis concentrations likely reflect fluid losses during dialysis. Two patients undergoing conventional hemodialysis had extraction ratios of 20% and 25% but the range was wide (extraction ratios for all 5 patients in the study were: 1%, 3%, 7%, 20%, and 25%). Study authors concluded that dosage adjustment of dolutegravir is not necessary in patients undergoing dialysis, as postdialysis concentrations remained well above a protein-adjusted IC90 value of 0.064 µg/mL. Of note, this reference IC90 was derived from a dolutegravir dose-ranging pharmacokinetic study in integrase inhibitor-naive patients with normal renal function.
Dolutegravir concentrations in this small sample were similar to those seen in the treatment-naive patients in the SPRING-1 and SPRING-2 studies of dolutegravir. Yet an earlier study conducted by the manufacturer found that subjects with severe renal dysfunction (CrCl <30 mL/min, not on dialysis) had lower dolutegravir AUC (40% lower) and Cmax (23% lower) compared with healthy controls.
Clinical Bottom Line
In patients who have severe renal failure or are on dialysis, drug disposition can be unpredictable owing to possible compensatory increases in nonrenal metabolism and alterations in protein binding.
The study presented at CROI by Moltó et al. suggests that, although dolutegravir concentrations may be reduced by dialysis, the decreases should not be clinically significant, at least for patients whose HIV does not have resistance mutations to dolutegravir. However, dolutegravir should be used with caution in hemodialysis patients who previously have been treated with integrase inhibitors and who have documented or clinically suspected dolutegravir resistance mutations, because the potential for a reduced AUC may lead to treatment failure.
Moltó J, Graterol F, Miranda C, et. al. Minimal Removal of Dolutegravir by Hemodialysis in HIV-Infected Patients. In: Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston. Poster 432.
Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as a 10-day monotherapy in HIV-1-infected adults. AIDS. 2011 Sep 10;25(14):1737-45.
Weller S, Borland J, Shen S, et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol. 2014 Jan;70(1):29-35.