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Stott, Katharine E, Moyo, Melanie, Ahmadu, Ajisa, Kajanga, Cheusisime, Gondwe, Ebbie, Chimang’anga, Wezzie, Chasweka, Madalitso, Leeme, Tshepo B, Molefi, Mooketsi, Chofle, Awilly, Bidwell, Gabriella, Changalucha, John, Unsworth, Jenny, Jimenez-Valverde, Ana, Lawrence, David S, Mwandumba, Henry 
ORCID: https://orcid.org/0000-0003-4470-3608, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Harrison, Thomas S, Jarvis, Joseph N, Hope, William and Märtson, Anne-Grete
(2022)
'Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis'. The Journal of Antimicrobial Chemotherapy, Vol 78, Issue 1, pp. 276-283.
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Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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 |
|---|---|
| Subjects: | QV Pharmacology > QV 38 Drug action. WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 245 Meningococcal infections WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503 Acquired immunodeficiency syndrome. HIV infections WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.5 Complications WL Nervous System > WL 200 Meninges. Blood-brain barrier |
| Faculty: Department: | Clinical Sciences & International Health > Clinical Sciences Department |
| Digital Object Identifer (DOI): | https://doi.org/10.1093/jac/dkac389 |
| SWORD Depositor: | JISC Pubrouter |
| Depositing User: | JISC Pubrouter |
| Date Deposited: | 20 Dec 2022 17:08 |
| Last Modified: | 10 Mar 2023 13:58 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/21578 |
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