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

Katharine E. Stott; Melanie Moyo; Ajisa Ahmadu; Cheusisime Kajanga; Ebbie Gondwe; Wezzie Chimang'anga; Madalitso Chasweka; Tshepo B. Leeme; Mooketsi Molefi; Awilly Chofle; Gabriella Bidwell; John Changalucha; Jenny Unsworth; Ana Jimenez-Valverde; David S. Lawrence; Henry Mwandumba; David Lalloo; Thomas S. Harrison; Joseph N. Jarvis; William Hope; Anne Grete Märtson

doi:10.1093/jac/dkac389

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

Katharine E. Stott, Melanie Moyo, Ajisa Ahmadu, Cheusisime Kajanga, Ebbie Gondwe, Wezzie Chimang'anga, Madalitso Chasweka, Tshepo B. Leeme, Mooketsi Molefi, Awilly Chofle, Gabriella Bidwell, John Changalucha, Jenny Unsworth, Ana Jimenez-Valverde, David S. Lawrence, Henry Mwandumba, David Lalloo, Thomas S. Harrison, Joseph N. Jarvis, William HopeAnne Grete Märtson

Clinical Sciences

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	276-283
Number of pages	8
Journal	Journal of Antimicrobial Chemotherapy
Volume	78
Issue number	1
Early online date	22 Nov 2022
DOIs	https://doi.org/10.1093/jac/dkac389
Publication status	Published - 22 Nov 2022

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Stott, K. E., Moyo, M., Ahmadu, A., Kajanga, C., Gondwe, E., Chimang'anga, W., Chasweka, M., Leeme, T. B., Molefi, M., Chofle, A., Bidwell, G., Changalucha, J., Unsworth, J., Jimenez-Valverde, A., Lawrence, D. S., Mwandumba, H., Lalloo, D., Harrison, T. S., Jarvis, J. N., ... Märtson, A. G. (2022). Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis. Journal of Antimicrobial Chemotherapy, 78(1), 276-283. https://doi.org/10.1093/jac/dkac389

@article{4badfa39178e4311b579ff95fb15e6ec,

title = "Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis",

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.",

author = "Stott, \{Katharine E.\} and Melanie Moyo and Ajisa Ahmadu and Cheusisime Kajanga and Ebbie Gondwe and Wezzie Chimang'anga and Madalitso Chasweka and Leeme, \{Tshepo B.\} and Mooketsi Molefi and Awilly Chofle and Gabriella Bidwell and John Changalucha and Jenny Unsworth and Ana Jimenez-Valverde and Lawrence, \{David S.\} and Henry Mwandumba and David Lalloo and Harrison, \{Thomas S.\} and Jarvis, \{Joseph N.\} and William Hope and M{\"a}rtson, \{Anne Grete\}",

year = "2022",

month = nov,

day = "22",

doi = "10.1093/jac/dkac389",

language = "English",

volume = "78",

pages = "276--283",

journal = "Journal of Antimicrobial Chemotherapy",

issn = "0305-7453",

publisher = "Oxford University Press",

number = "1",

}

Stott, KE, Moyo, M, Ahmadu, A, Kajanga, C, Gondwe, E, Chimang'anga, W, Chasweka, M, Leeme, TB, Molefi, M, Chofle, A, Bidwell, G, Changalucha, J, Unsworth, J, Jimenez-Valverde, A, Lawrence, DS, Mwandumba, H , Lalloo, D, Harrison, TS, Jarvis, JN, Hope, W & Märtson, AG 2022, 'Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis', Journal of Antimicrobial Chemotherapy, vol. 78, no. 1, pp. 276-283. https://doi.org/10.1093/jac/dkac389

TY - JOUR

T1 - Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis

AU - Stott, Katharine E.

AU - Moyo, Melanie

AU - Ahmadu, Ajisa

AU - Kajanga, Cheusisime

AU - Gondwe, Ebbie

AU - Chimang'anga, Wezzie

AU - Chasweka, Madalitso

AU - Leeme, Tshepo B.

AU - Molefi, Mooketsi

AU - Chofle, Awilly

AU - Bidwell, Gabriella

AU - Changalucha, John

AU - Unsworth, Jenny

AU - Jimenez-Valverde, Ana

AU - Lawrence, David S.

AU - Mwandumba, Henry

AU - Lalloo, David

AU - Harrison, Thomas S.

AU - Jarvis, Joseph N.

AU - Hope, William

AU - Märtson, Anne Grete

PY - 2022/11/22

Y1 - 2022/11/22

N2 - 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.

AB - 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.

U2 - 10.1093/jac/dkac389

DO - 10.1093/jac/dkac389

M3 - Article

SN - 0305-7453

VL - 78

SP - 276

EP - 283

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 1

ER -

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

Abstract

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