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No Bictegravir Dose Adjustment With Liver or Kidney Impairment
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18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
People with moderate liver impairment or severe kidney impairment will not have to adjust their dose of bictegravir, an investigational HIV integrase inhibitor being coformulated with emtricitabine and tenofovir alafenamide, according to results of two open-label parallel-group studies [1].
Bictegravir is metabolized mainly by the liver via the CYP3A4 and UGT1A1 enzymes; elimination by the kidney is negligible. Gilead Sciences researchers conducted this study to compare bictegravir pharmacokinetics in people with mild liver impairment (Child-Pugh-Turcotte score 7 to 9) or severe kidney impairment (creatinine clearance 15 to 29 mL/min) versus people with normal liver or kidney function.
The liver function trial matched 10 people with moderate liver impairment by age, gender, and body mass index (BMI) to 10 people with normal liver function. The kidney function trial matched 10 people with severe impairment by age, gender, and BMI to 8 people without impairment. All participants took a single 75-mg dose of bictegravir after a moderate-fat breakfast and had intensive sampling over the next 144 hours. The analysis considered a bictegravir level potentially clinically meaningful if there was a 100% or greater difference in 90% confidence intervals for that value.
All adverse events were grade 1. Three study drug-related adverse events occurred in people with moderate liver impairment (headache and somnolence) and one in people with severe kidney impairment (nausea). There were no clinically meaningful lab value changes.
Bictegravir levels were largely similar in people with or without moderate liver impairment. Average bictegravir area under the concentration-time curve (AUC) was about 41% lower in the impaired group, but free bictegravir AUC was only 23% lower. Neither bictegravir AUC nor bictegravir maximum concentration (Cmax) correlated with components of the Child-Pugh-Turcotte score (such as albumin, total bilirubin, and promthrombin time).
Bictegravir AUC was about 27% lower in people with versus without severe kidney impairment, but free bictegravir AUC was equivalent in the two groups. Neither bictegravir AUC nor bictegravir Cmax correlated with estimated glomerular filtration rate.
The Gilead team concluded that moderate liver impairment or severe renal impairment did not produce clinically relevant changes in exposure of the integrase inhibitor bictegravir. They believe no bictegravir dose adjustments will be needed in these groups.
CROI: Randomized Trial of Bictegravir or Dolutegravir with FTC/TAF for Initial HIV Therapy - (02/16/17)
Gilead Submits New Drug Application to U.S. Food and Drug Administration for Fixed-Dose Combination of Bictegravir, Emtricitabine and Tenofovir Alafenamide for HIV Treatment - (06/13/17)
Reference
1. Zhang H, Shao Y, Garner W, et al. The effect of hepatic or renal impairment on bictegravir pharmacokinetics. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract P_27.
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