Infants bear a significant malaria burden but are usually excluded from participating in early dose optimisation studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants’ exclusion from early-phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under or overdosing. Population pharmacokinetic-pharmacodynamic (PK-PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimised antimalarial dosing in this complex and at-risk yet understudied subpopulation. In this review, we reflect on what PK-PD modelling can do in programmatic settings of most malaria-endemic areas and how it can be used to inform antimalarial dose optimisation for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimisation studies in infants, and examples of how PK-PD modelling has previously informed antimalarial dose optimisation in this subgroup. Additionally, we have discussed the limitations and gaps of PK-PD modelling when used for dose optimisation in infants and best practices for using population PK-PD methods in this subgroup.

BACKGROUND AND PURPOSE Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. EXPERIMENTAL APPROACH Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. KEY RESULTS Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the dominant metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure defined by LC-MS/MS and NMR indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1 was produced by CYP3A4 and CYP3A5, and that M3 and M6 were produced by CYP3A4. CONCLUSIONS AND IMPLICATIONS Demethylated and hydroxylated ivermectin are the main human metabolites in vivo. Further study to characterize their pharmacokinetic properties and mosquito-lethal activity is now needed.