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.

Abstract: Background. Doxorubicin chemotherapy drug , use is limited by it’s potential to cause cardiotoxicity. In resource poor settings, like Malawi, monitoring of doxorubicin cardiotoxicity is not routinely conducted in cancer patients and the incidence of doxorubicin cardiotoxicity is not known. Methods. Children aged 3 months to 18 years with cancer were prospectively enrolled from the paediatric oncology ward and followed up from January 2016 to June 2019. Transthoracic echocardiographic monitoring of left ventricular ejection fraction (LVEF) was done at baseline, one month, six months and a year after completion of therapy. Cardiotoxicity was defined as a decline in LVEF of ≥10% to a final value of <50%, and an overall incidence risk of developing cardiotoxicity was estimated. A one-way analysis of variance was conducted to compare baseline LVEF with that measured during follow up intervals. Findings. A total of 91 children were enrolled into the study, 74% (68/91) were male, and 67% (62/91) were aged 5 months to 14 years. Burkitt lymphoma was diagnosed in 41% (38/91) of the children. No one experienced cardiotoxicity during the study period. However, of 77 children who had at least one follow up, five children 6·54% (95% CI: 2.1-14.5) experienced a reduction in LVEF of >10%, though not to a final value of <50%. No deterioration of systolic function was found among 20 children who had completed follow up. (F= 2·43, p-value=0·07). Interpretation. In this cohort, there were no observed cardiotoxic events associated with doxorubicin administration as per pre-defined criterion