Nifurtimox for Treatment of Chagas Disease in Pediatric Patients: the Challenges of Applying Pharmacokinetic-Pharmacodynamic Principles to Dose Finding.
efficacy
exposure
nifurtimox
pediatric
safety
Journal
The AAPS journal
ISSN: 1550-7416
Titre abrégé: AAPS J
Pays: United States
ID NLM: 101223209
Informations de publication
Date de publication:
24 08 2022
24 08 2022
Historique:
received:
19
04
2022
accepted:
02
08
2022
entrez:
24
8
2022
pubmed:
25
8
2022
medline:
27
8
2022
Statut:
epublish
Résumé
The antiparasitic drug nifurtimox was approved in the USA in 2020 for the treatment of patients with Chagas disease aged less than 18 years and weighing at least 2.5 kg, based on outcomes from the phase 3 CHICO study. Accordingly, pediatric patients with Chagas disease take nifurtimox thrice daily with food at one of two body weight-adjusted dose ranges. We investigated possible relationships between pharmacokinetic (PK) data, and pharmacodynamic efficacy and safety data collected in an analysis population of 111 participants in CHICO, using a published population PK model to estimate nifurtimox exposure at the patient level. Pediatric exposure to nifurtimox was benchmarked against levels of nifurtimox exposure known to be effective in adults with Chagas disease. Given the complex dosing regimen for nifurtimox, we also modeled nifurtimox exposure associated with simpler dosing strategies. We found no relationship between exposure to nifurtimox and efficacy measures (e.g., serological response to treatment), or between exposure and safety outcomes (including typical adverse events, e.g., headache, decreased appetite, nausea/vomiting). The analysis population appeared to represent the overall CHICO population based on the similarity of their baseline characteristics and the profiles of adverse events in the two groups. Modeled exposure based on the dosing regimen in CHICO was within the reference range derived from phase 1 data in adults. The relationship between nifurtimox exposure and cure is complex; a simplified pediatric dosing regimen is unlikely to be beneficial.
Identifiants
pubmed: 36002604
doi: 10.1208/s12248-022-00742-w
pii: 10.1208/s12248-022-00742-w
doi:
Substances chimiques
Nifurtimox
M84I3K7C2O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
92Informations de copyright
© 2022. The Author(s).
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