Amphotericin B cholesteryl sulfate clinical pharmacology

# Clinical Pharmacology

### Pharmacokinetics
The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were studied in 51 bone marrow transplant patients with systemic fungal infections. The median (range) age and weight of those patients were 32 (3 to 52) years and 69.5 (14 to 116) kg, respectively. AMPHOTEC doses ranged from 0.5 to 8.0 mg/kg/day. The assay used in this study to measure amphotericin B in plasma does not distinguish amphotericin B that is complexed with cholesteryl sulfate from uncomplexed amphotericin B. A population modeling approach was used to estimate pharmacokinetic parameters (see table). The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were best described by an open, two compartment structural model. The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were nonlinear. Steady state volume of distribution (Vss) and total plasma clearance (CLt) increased with escalating doses, resulting in less than proportional increases in plasma concentration over a dose range of 0.5 to 8.0 mg/kg/day. The increased volume of distribution probably reflected uptake by tissues. The covariates of body weight and dose level accounted for a substantial portion of the variability of the pharmacokinetic estimates between patients. The unexplained variability in clearance was 26%. Based on the population model developed for these patients, pharmacokinetic parameters were predicted for two doses of AMPHOTEC and are provided in the following table:
In addition, the pharmacokinetics of amphotericin B, administered as amphotericin B deoxycholate, were studied in 15 patients in whom amphotericin B deoxycholate was administered for the treatment of aspergillus infections or empirical therapy. The median (range) age and weight for these patients were 21 (4 to 66) years and 60 (19 to 117) kg, respectively. A population modeling approach was used to estimate the pharmacokinetic parameters. The pharmacokinetics of amphotericin B, administered as amphotericin B deoxycholate, was best described as an open, two-compartment model with linear elimination.
The predicted pharmacokinetic parameters are provided in the following table:
An analytical assay that is able to distinguish between amphotericin B in the AMPHOTEC complex and amphotericin B which is not complexed to cholesteryl sulfate was used to analyze samples from a study of 25 patients who were either immunocompromised with aspergillosis or both febrile and neutropenic. Following a 1 mg/kg/hour infusion, 25  18% (mean  SD) of the total amphotericin B concentration measured in plasma was in the AMPHOTEC complex, dropping to 9.3  7.9% at 1 hour and 7.5  9.3% at 24 hours after the end of the infusion.

### Pharmacokinetics in Special Populations
A population modeling approach was used to assess the effect of renal function, hepatic function, and age on the pharmacokinetics of AMPHOTEC in 51 patients receiving bone marrow transplants as described earlier.
Renal Impairment: The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were not related to baseline serum creatinine clearance in the population studied; the median (range) creatinine clearance for this population was 74.0 (range: 35 - 202) mL/min/70 kg. The effect of more severe renal impairment on the pharmacokinetics of AMPHOTEC has not been studied.
Hepatic Impairment: The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were not related to baseline liver function, as determined by liver enzymes and total bilirubin. For the population tested, the mean  SD values for AST and total Bilirubin were 59.4  70.0 IU/mL and 3.5  3.7 mg/dL, respectively. The effect of more severe hepatic impairment on the pharmacokinetics of AMPHOTEC has not been studied.
Age: The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were not related to the age of the patient. The median (range) age for the population in this study was 32 (3 to 52) years.