Single-dose pharmacokinetics of the cholesteryl sulfate complex of amphotericin B in critically ill patients with cholestatic liver failure

Introduction

Investigations on the pharmacokinetics and elimination of amphotericin B (AMB) lipid formulations in liver impairment have so far been lacking. In the present clinical study the pharmacokinetics of the cholesteryl sulfate complex of AMB was assessed in critically ill patients with cholestatic liver failure.

Methods

Time–concentration profiles were determined in critically ill patients with cholestatic liver failure and in critically ill patients with normal hepatic function requiring cholesteryl sulfate complex of AMB for invasive fungal infections. The lipid-associated and liberated fraction of AMB were separated by solid-phase extraction and subsequently quantified by high-performance liquid chromatography.

Results

Three patients with impaired and three patients with normal hepatic function on day 1 of ABCD therapy have so far been enrolled. After a single dose of ABCD (2.46 ± 0.54 mg vs 2.94 ± 1.47 mg/kg in the impaired-liver group compared with the control group), the maximum concentration in patients with impaired liver function was fourfold increased compared with the control group (1.98 ± 0.61 vs 0.52 ± 0.12 μg/ml for total AMB (P < 0.05), 1.25 ± 0.58 vs 0.46 ± 0.14 μg/ml for the liberated fraction (P < 0.05), 0.74 ± 0.05 vs 0.06 ± 0.02 μg/ml for the lipid-associated fraction (P < 0.05)). The clearance was slower in the investigational group (0.15 ± 0.09 vs 0.38 ± 0.19 l/hour/kg for total AMB, 0.22 ± 0.10 vs 0.38 ± 0.19 l/hour/kg for the liberated AMB fraction (P < 0.05) and 0.52 ± 0.45 vs 17.84 ± 15.45 l/hour/kg for lipid-associated AMB (P < 0.05)). The volume of distribution at steady state was significantly decreased (2.17 ± 0.58 vs 9.78 ± 2.99 l/kg for total AMB (P < 0.05), 3.09 ± 0.88 vs 10.39 ± 2.70 l/kg for liberated AMB (P < 0.05) and 8.18 ± 3.47 vs 83.27 ± 64.98 l/kg for lipid-associated AMB (P < 0.05)).

Conclusion

The elimination of ABCD appears to be delayed in cholestatic liver failure, particularly that of the lipid-associated fraction. More pharmacokinetic data are required to establish reliable dose recommendations for ABCD in patients with liver failure.