Pharmacokinetics and Pharmacodynamics of Liposomal Amphotericin B (LAmB) for Cryptococcal Meningitis. A Single High Dose of Liposomal Amphotericin B is as Efficacious as Daily Dosing Regimens

Ref ID: 18741

Author:

J. Livermore, PhD – Research Assistant1, L. O’Connor, MRes – MRes Student 1, A. Sharp, BSc – Research Assistant 1, L. Gregson, MSc – Research Assistant 1, J. Goodwin, BSc – Research Assistant 1, P. Warn, PhD – Senior Lecturer 1, T. Felton, MD – Clini

Author address:

1The Univ. of Manchester, Manchester, United Kingdom, 2Charles River Lab., Davis, CA.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Cryptococcal meningitis is a leading cause of infectious morbidity and mortality in patients with AIDS. LAmB is increasingly used. However, little is known about the PK-PD of LAmB or the optimal regimen for humans. There is no information on the shortest duration of therapy that still results in near maximal antifungal activity. Methods: A well-validated murine model of cryptococcal meningitis was used. Mice were infected i.v.. LAmB 3, 10 and 20 mg/kg/day was administered i.v. A serial sacrifice design was used. Drug concentrations in the plasma and cerebrum were measured using HPLC. The fungal burden in the cerebrum was estimated with quantitative counts. The time course of infection following a single dose of 20 mg/kg i.v. was compared with that resulting from 20 mg/kg/day i.v. The intracerebral distribution of amphotericin B was determined using immunohistochemistry using a monoclonal antibody against active drug. The PK and PD data were described using a mathematical model. Results: There was progressive logarithmic fungal growth in the cerebrum over a 7 day period. The PK in plasma and cerebrum were linear, with dose-dependent penetration of active drug into the brain. The administration of 3 mg/kg had negligible antifungal effect. Maximal antifungal activity was observed following the administration of 20 mg/kg/day. Immunohistochemistry demonstrated the accumulation of amphotericin B within the choroid plexus. The antifungal effect of 20 mg/kg administered once was indistinguishable from 20 mg/kg/day. The mathematical model accounted for the observed data. Conclusions: This study provides the experimental basis for identifying optimal antifungal regimens of LAmB in humans and innovative induction regimens that may potentially be used in poor resource settings.

Abstract Number: A-1944

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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