Population pharmacokinetics of lumefantrine and its metabolite, desbutyl-lumefantrine, in children under five years of age with malaria

Abstract

We developed a population pharmacokinetic model to characterize the Pharmacokinetics (PK) of lumefantrine and its active metabolite, desbutyl-lumefantrine, in children under 5 years. Data were available from 55 children treated for uncomplicated falciparum malaria with standard 3-day Artemether- Lumefantrine (AL) regimen. Combined sparse and intense PK sampling strategy was used to obtain venous samples for 28 days. Using NONMEM, a two-compartment linear pharmacokinetic model incorporating lag time with first order absorption characterized the PK of lumefantrine. Desbutyl-lumefantrine PK was also characterized with a two compartment model. Inter-subject variability in apparent Clearance (CL/F) was explained by Body Mass Index (BMI) and age, while weight partially explained variability in apparent volume of distribution of the central compartment (V2/F). Ontogeny in CYP3A4, the isozyme metabolizing lumefantrine, was incorporated into the age component of lumefantrine CL/F model. Incorporation of BMI into CL/F model explained variability due to weight and stunting. For lumefantrine typical inter-compartment clearance (Q/F), CL/F, V2/F for a typical subject weighing 13.0 kg and BMI 16.62 kg/m2 , and apparent volume of distribution of peripheral compartment (V3/F) were 0.176 L/hr, 3.19 L/hr, 28.1 L, and 58.4 L, respectively. Lumefantrine CL/F was higher in children ≤2 year compared to those >2 years, notably decreased with increasing BMI (-1.10) and age from two to just less than five years (CL/FAGE: -0.423 (-0.648, -0.198)). Results indicate lumefantrine CL/F is a function of age and BMI. Our findings provide structural basis for future evaluation of rational AL dosing guidelines among under five year olds.