Population Pharmacokinetic-Pharmacodynamic Model of Oxfendazole in Healthy Adults in a Multiple Ascending Dose and Food Effect Study and Target Attainment Analysis.
Antimicrob Agents Chemother
; 66(1): e0143221, 2022 01 18.
Article
em En
| MEDLINE
| ID: mdl-34606333
ABSTRACT
Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics, and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a life span indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg of body weight once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos