Understanding Drug Exposure and Trichuris trichiura Cure Rates: A Pharmacometric Approach for Albendazole-Ivermectin Co-medication in Tanzania and Côte d'Ivoire.
Drugs R D
; 24(2): 331-340, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-39034337
ABSTRACT
BACKGROUND AND OBJECTIVE:
Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d'Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate.METHODS:
Pharmacokinetic data from studies in Tanzania and Côte d'Ivoire in adolescents (aged 12-19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis.RESULTS:
Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate.CONCLUSIONS:
Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d'Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tricuriasis
/
Trichuris
/
Ivermectina
/
Albendazol
/
Quimioterapia Combinada
Límite:
Adolescent
/
Adult
/
Animals
/
Child
/
Female
/
Humans
/
Male
País/Región como asunto:
Africa
Idioma:
En
Revista:
Drugs R D
Asunto de la revista:
TERAPIA POR MEDICAMENTOS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Sudáfrica