Pharmacokinetics (PK) and Pharmacodynamics (PD) of Liposomal Amphotericin B (LAmB) and Flucytosine (5FC) Against Cryptococcus neoformans in a Murine Model of Cryptococcal Meningitis

Ref ID: 18740

Author:

L. O’Connor, MRes – Student, J. Livermore, PhD – Research Assistant, A. Sharp, BSc – Research Assistant, J. Goodwin, BSc – Research Assistant, T. W. Felton, MD – Clinical Fellow, S. J. Howard, PhD – Research Associate, W. W. Hope, MD PhD – Professor

Author address:

The Univ. of Manchester, Manchester, United Kingdom.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Cryptococcal meningitis is a lethal AIDS-associated infection. Lipid formulations of AmB (LAmB) are increasingly used. However, there is no information on the pharmacodynamics of LAmB in combination with 5FC. Methods: A well-validated murine model of cryptococcal meningitis was used to determine the PK-PD relationships of regimens of LAmB and 5FC alone and in combination. Dosages of LAmB and 5FC of 3-20mg/kg/day i.v. and 25-100 mg/kg Q8 hrs orally, respectively were studied. Plasma and cerebral concentrations of the both agents were measured using HPLC. Cerebral fungal burden was quantified by plating tissue homogenates. A mathematical model was developed that linked the plasma PK, cerebral PK, and the observed antifungal effect in the brain of drugs alone and in combination. The interaction effect was modeled by allowing concentrations of the second drug to affect the maximal rate of killing exerted by the first drug. Results: There was progressive logarithmic increase in cerebral fungal burden of untreated mice from days 0-4, followed by persistent cerebral infection. LAmB and 5FC penetrated the CNS in a dose-dependent manner. There was a dose-dependent antifungal effect. A LAmB regimen of 20 mg/kg/day i.v. resulted in a a 3 log drop, whereas a 5FC regimen of 100 mg/kg every 8 hrs resulted in a 2 log drop. The combination of both agents resulted in an additional antifungal effect, but only for regimens of LAmB associated with sub-maximal antifungal activity. A combination of LAmB 3 mg/kg/day i.v. and 5FC 100 mg/kg Q8hrs orally resulted in comparable activity to LAmB 20 mg/kg/day i.v. The mathematical model accounted for the observed PK and PD data. Conclusion: This study provides the experimental basis for optimal combination induction regimens of LAmB and 5FC in humans and can be used to identify the smallest dosage of drugs in combination that are still associated with near-maximal antifungal activity.

Abstract Number: A-1942

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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