Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria.
Adolescent
Adult
Aged
Aged, 80 and over
Amodiaquine
/ administration & dosage
Antimalarials
/ pharmacokinetics
Artemisinins
/ administration & dosage
Child
Child, Preschool
Chromatography, Liquid
/ methods
Drug Combinations
Female
Ghana
Humans
Infant
Malaria, Falciparum
/ parasitology
Male
Middle Aged
Tandem Mass Spectrometry
/ methods
Young Adult
Amodiaquine
Artesunate
Fixed-dose combination
Ghana
Infants
P. falciparum malaria
Parasite density
Pharmacokinetics
Underweight-for-age
Young children
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
06 Jan 2021
06 Jan 2021
Historique:
received:
03
07
2020
accepted:
15
12
2020
entrez:
7
1
2021
pubmed:
8
1
2021
medline:
10
7
2021
Statut:
epublish
Résumé
Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups. A sensitive and selective LC-MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine. The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1-4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78-0.98), p = 0.021]. Amodiaquine exposure (median AUC Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.
Sections du résumé
BACKGROUND
BACKGROUND
Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups.
METHODS
METHODS
A sensitive and selective LC-MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine.
RESULTS
RESULTS
The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1-4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78-0.98), p = 0.021]. Amodiaquine exposure (median AUC
CONCLUSIONS
CONCLUSIONS
Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.
Identifiants
pubmed: 33407454
doi: 10.1186/s12936-020-03553-6
pii: 10.1186/s12936-020-03553-6
pmc: PMC7788723
doi:
Substances chimiques
Antimalarials
0
Artemisinins
0
Drug Combinations
0
amodiaquine, artesunate drug combination
0
Amodiaquine
220236ED28
desethylamodiaquine
79352-78-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
18Subventions
Organisme : Bill and Melinda Gates Foundation
ID : 48363.01
Commentaires et corrections
Type : ErratumIn
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