Comparison between physiologically based pharmacokinetic and population pharmacokinetic modelling to select paediatric doses of gepotidacin in plague

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 (R), 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, similar to 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 C-max and AUC((0-tau)) 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 C-max for a given dose, but the C-max 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.

Automated summary

PBPK and PopPK models were developed to predict effective doses of gepotidacin in pediatric patients for treating pneumonic plague caused by Yersinia pestis. Body weight was identified as a key covariate affecting gepotidacin clearance. The models showed differences in dose predictions based on weight and age, with PopPK potentially suboptimal for very young children due to enzyme maturation considerations.