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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis
Journal of Antimicrobial Chemotherapy, Volume 78, No. 11, Year 2023
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Description
Objectives: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14-and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response. Methods: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults. Results: Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-Treatment AUC0-24h 187 (162-203) and 242 (217-328) μg·h/mL, respectively], but were both within the IQR of end-of-Treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-Treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) μg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults. Conclusions: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-Toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients. © 2023 The Author(s). Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
Authors & Co-Authors
Verrest, Luka
Netherlands, Amsterdam
Antoni Van Leeuwenhoek Ziekenhuis
Roseboom, Ignace C.
Netherlands, Amsterdam
Antoni Van Leeuwenhoek Ziekenhuis
Wasunna, Monique K.
Kenya, Nairobi
Drugs for Neglected Diseases Initiative
Mbui, Jane K.
Kenya, Nairobi
Kenya Medical Research Institute
Njenga, Simon Njoroge
Kenya, Nairobi
Kenya Medical Research Institute
Musa, Ahmed Mudawi
Sudan, Khartoum
Khartoum University
Olobo, Joseph Okao
Uganda, Kampala
Makerere University
Mohammed, Rezika
Ethiopia, Gondar
University of Gondar
Ritmeijer, Koert
Switzerland, Geneva
Medecins Sans Frontieres
Huitema, Alwin D.R.
Netherlands, Amsterdam
Antoni Van Leeuwenhoek Ziekenhuis
Netherlands, Utrecht
Universiteit Utrecht
Netherlands, Utrecht
Princess Máxima Center for Pediatric Oncology
Solomos, Alexandra
Switzerland, Geneva
Drugs for Neglected Diseases Initiative
Alves, Fabiana Piovesan
Switzerland, Geneva
Drugs for Neglected Diseases Initiative
Dorlo, Thomas P.C.
Netherlands, Amsterdam
Antoni Van Leeuwenhoek Ziekenhuis
Sweden, Uppsala
Uppsala Universitet
Statistics
Citations: 1
Authors: 13
Affiliations: 11
Identifiers
Doi:
10.1093/jac/dkad286
ISSN:
03057453
Research Areas
Cancer
Maternal And Child Health
Study Design
Cross Sectional Study
Study Approach
Quantitative
Study Locations
Ethiopia
Kenya
Sudan
Uganda