title: Population pharmacokinetics of conventional and intermittent dosing of liposomal amphotericin B in adults: a first critical step for rational design of innovative regimens.
abstract: There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P = 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.
authors.affiliation: School of Translational Medicine, The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom. william.hope@manchester.ac.uk
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.forename: Joanne
authors.initials: J
authors.lastname: Goodwin
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Felton
authors.forename: Michael
authors.initials: M
authors.lastname: Ellis
authors.forename: David A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D000293:Adolescent; D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B