Optimization of Malaria Treatment Strategies: A Pharmacokinetic and Pharmacodynamic Analysis of Artemether-Lumefantrine in the Context of Pediatrics and HIV

Malaria remains a leading cause of morbidity and mortality worldwide, with young children at particular risk for severe, or complicated disease. The artemisinin-based combination therapies (ACTs) are the first-line treatment for uncomplicated (i.e., non-severe) malaria, but optimal dosing regimens are yet unclear for the most vulnerable populations, such as young children and those with potential drug-drug interactions for treatment of co-morbidities, like HIV. Suboptimal dosing not only diminishes clinical responses, but also exposes parasites to subtherapeutic levels of antimalarials, which may select for resistant parasites. For example, resistance to artemether-lumefantrine (AL), a commonly prescribed ACT, is an emerging problem in Africa. Thus, the goal of this dissertation work was to identify ways to optimize dosing in these populations in order to protect the utility of ACTs. The specific aims of this work were to evaluate the pharmacologic and clinical benefits of extending AL malaria treatment duration from the standard 3-day (6 dose) regimen to a 5-day regimen (10 dose) in young HIV-uninfected children (Aim 1, Chapter 2) and HIV-infected children on efavirenz (EFV)-based antiretroviral therapy (ART) (Aim 2, Chapter 3). As EFV has potent metabolic inductive effects shown to result in lower AL exposure, in Aim 2 an extended regimen was evaluated as an attempt to compensate for this drug-drug interaction. The overall goal of the study was to determine the impact of extended duration treatment on the pharmacokinetics (PK) and pharmacodynamics (PD) of AL. Samples collected as part of a prospective, randomized, open-label phase 4 trial of uncomplicated malaria pediatric patients in Uganda with and without HIV co-infection were used to quantify (1) artemether, (2) active metabolite, dihydroartemisinin (DHA), (3) lumefantrine (LF), and (4) active metabolite, desbutyl-lumefantrine (DBL) plasma concentrations. Children received malaria treatment with standard 3-day (6-dose) or extended 5-day (10-dose) AL-based therapy. A combination of intensive and population PK sampling approaches was utilized to determine drug exposure. PK estimates were then linked to clinical outcomes (e.g., recurrent parasitemia) and assessed over a 42-day follow-up period for the PD analyses. Overall, our analyses demonstrated that extended (5-day) duration of AL-based antimalarial therapy significantly increased AL and AL-metabolite exposure in HIV-uninfected children. These findings included statistically significant higher exposure of the artemisinins and long acting LF and DBL with extended 5-day therapy. In particular, higher LF concentrations were associated with a 46% and 42% lower risk of recurrent parasitemia at 28 and 42 days, respectively. In addition, weight-based associations were observed for LF among HIV-uninfected children; participants in the lowest weight-band had the lowest AL plasma concentrations. Among HIV-infected children, 5 days of AL successfully compensated for the EFV-driven cytochrome P450 (CYP) 3A4 induction effect and resulted in LF exposure that was equivalent to that seen in HIV-uninfected children given 3 days of AL. Collectively, this dissertation contributes to the limited PK/PD data for AL-based treatment regimens for uncomplicated malaria in children. Here, we studied an underrepresented, pediatric population to highlight the necessity for optimized dosing regimens (for example, among HIV-coinfected and low weight children). Given that this population makes up the majority of malaria-related morbidity and death, efforts to optimize AL-based treatment regimen dosing in these patients are likely to lead to improved malaria clinical outcomes worldwide