Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis



Stott, Katharine E ORCID: 0000-0001-7079-7957, Moyo, Melanie, Ahmadu, Ajisa, Kajanga, Cheusisime, Gondwe, Ebbie, Chimang'anga, Wezzie, Chasweka, Madalitso, Leeme, Tshepo B, Molefi, Mooketsi, Chofle, Awilly
et al (show 11 more authors) (2023) Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 78 (1). pp. 276-283.

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Abstract

<h4>Background</h4>Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis.<h4>Methods</h4>Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed.<h4>Results</h4>A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363)  L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351)  h-1, and from peripheral to central compartment 2.951 (4.070)  h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis.<h4>Conclusions</h4>This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Item Type: Article
Uncontrolled Keywords: Humans, Cryptococcus neoformans, Meningitis, Cryptococcal, HIV Infections, Meningoencephalitis, Antifungal Agents
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 25 Nov 2022 11:48
Last Modified: 02 Feb 2024 01:06
DOI: 10.1093/jac/dkac389
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3166382