Population pharmacokinetics of conventional and intermittent dosing of liposomal amphotericin B in adults: A first critical step for rational design of innovative regimens

William W. Hope, Joanne Goodwin, Timothy W. Felton, Michael Ellis, David A. Stevens

    Research output: Contribution to journalArticlepeer-review

    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. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
    Original languageEnglish
    Pages (from-to)5303-5308
    Number of pages5
    JournalAntimicrobial Agents and Chemotherapy
    Volume56
    Issue number10
    DOIs
    Publication statusPublished - Oct 2012

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