Comparison between physiologically based pharmacokinetic and population pharmacokinetic modelling to select paediatric doses of gepotidacin in plague.
Br J Clin Pharmacol
; 88(2): 416-428, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34289143
ABSTRACT
AIMS:
To develop physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models to predict effective doses of gepotidacin in paediatrics for the treatment of pneumonic plague (Yersinia pestis).METHODS:
A gepotidacin PBPK model was constructed using a population-based absorption, distribution, metabolism and excretion simulator, Simcyp®, with physicochemical and in vitro data, optimized with clinical data from a dose-escalation intravenous (IV) study and a human mass balance study. A PopPK model was developed with pooled PK data from phase 1 studies with IV gepotidacin in healthy adults.RESULTS:
For both the PopPK and PBPK models, body weight was found to be a key covariate affecting gepotidacin clearance. With PBPK, ~90% of the predicted PK for paediatrics fell between the 5th and 95th percentiles of adult values except for subjects weighing ≤5 kg. PopPK-simulated paediatric means for Cmax and AUC(0-τ) were similar to adult exposures across various weight brackets. The proposed dosing regimens were weight-based for subjects ≤40 kg and fixed-dose for subjects >40 kg. Comparison of observed and predicted exposures in adults indicated that both PBPK and PopPK models achieved similar AUC and Cmax for a given dose, but the Cmax predictions with PopPK were slightly higher than with PBPK. The two models differed on dose predictions in children <3 months old. The PopPK model may be suboptimal for low age groups due to the absence of maturation characterization of drug-metabolizing enzymes involved with clearance in adults.CONCLUSIONS:
Both PBPK and PopPK approaches can reasonably predict gepotidacin exposures in children.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peste
Tipo de estudo:
Prognostic_studies
Limite:
Child
/
Humans
/
Infant
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos