Physiologically based pharmacokinetic modelling to predict artemether and lumefantrine exposure in neonates weighing less than 5 kg treated with artemether-lumefantrine to supplement the clinical data from the CALINA study.

Background: Evidence-based recommendations for malaria treatment in patients weighing < 5 kg are lacking as a consequence of differences in pharmacokinetics due to age and/or body weight (BW), and recruitment challenges in conducting trials in this population. A physiologically based pharmacokinetic (PBPK) model was developed and validated to predict artemether and lumefantrine concentrations in patients < 5 kg BW aged 1-28 days. The model predictions supplemented data from a trial (CALINA; NCT04300309) with an optimized dose of artemether-lumefantrine (5 mg artemether: 60 mg lumefantrine) in patients < 5 kg with Plasmodium falciparum malaria.

Methods: PBPK models of artemether and lumefantrine were developed using Simcyp (Version 22) and validation was performed using historical data from adults and paediatric patients. To compare model-predicted and observed values, populations were matched to clinical trial populations (ranging from adults to infants) for patient numbers and demographics. The models were applied to predict artemether maximal concentration (C_max) and lumefantrine C_max and Day 7 concentration (C_168h) in neonates of < 5 kg BW aged 1-28 days, and for subgroups aged 1-7, 8-14, and 15-28 days.

Results: Validated models for artemether and lumefantrine were used to predict plasma concentrations in neonates and young infants with BW < 5 kg after 3-day administration of 5 mg artemether and 60 mg lumefantrine twice daily with high confidence. The PBPK model using Upreti hepatic cytochrome P450 (CYP)3A4 ontogeny predicted observed artemether and lumefantrine exposure in infants and neonates better than Salem ontogeny. The predicted variability in neonates was comparable to or larger than the variability of observed concentrations in infants and older neonates in the CALINA study.

Conclusions: Based on the success of the PBPK models for artemether and lumefantrine in predicting drug concentrations in adults and children, including neonates, modelling and simulation results can be used with confidence to supplement the limited available data for neonates (1-28 days old) < 5 kg BW obtained from the CALINA study for this rarer and more difficult to recruit patient population.