Oil‐Fortified Maize Porridge Increases Absorption of Lumefantrine in Children with Uncomplicated Falciparum Malaria

Abstract

Artemether-lumefantrine (AL) is a first-line treatment for uncomplicated malaria. Absorption of lumefantrine (LUM) is fat dependent, and in children, intake is recommended with milk. We investigated whether oil-fortified maize porridge can be an alternative when milk is not available. In an open-label pharmacokinetic study, Ugandan children <5 years with uncomplicated Plasmodium falciparum malaria were randomized to receive standard six-dose AL treatment [one tablet (20 mgA/120 mg LUM) if <15 kg and two tablets if >15 kg] with milk (A) or maize porridge plus oil (B). Parametric two-sample t-test was used to compare relative oral LUM bioavailability. The primary end-point was LUM exposure till 8 hr after the first dose (AUC ). Secondary outcome included day 7 concentrations (d7 ), LUM exposure between days 7 and 28 (AUC ) and day 28 PCR-adjusted parasitological response. Evaluable children (n = 33) included 16 in arm A and 17 in arm B. The AUC was comparable between A and B [geometric mean (95% CI): 6.01 (3.26-11.1) versus 6.26 (4.5-8.43) hr*μg/mL, p = 0.9]. Less interindividual variability in AUC was observed in B (p = 0.01), but d7 and AUC were comparable. Children receiving two tablets had significantly higher exposure than those receiving one tablet [median d7 (505 versus 289 ng/mL, p = 0.02) and AUC (108 versus 41 hr*μg/mL, p = 0.006)]. One parasitological failure (d28 recrudescence) was observed. Our findings suggest that oil-fortified maize porridge can be an alternative to milk in augmenting absorption of LUM. The lower LUM exposure observed in children dosed with one AL tablet needs further attention.

Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

“…More advanced techniques are available to improve adherence, such as high-tech pill bottles, which can count number of times bottle opened. Although the study protocol required AL was taken with whole milk, milk may not be available in some resource-limited communities, alternative fatty food such as oil-fortified porridge might be used without compromising drug absorption[ 29 ]. In addition, in this study we did not measure the NVP concentrations, which would be helpful to verify these children had therapeutic NVP levels.…”

Solidification of Self-Emulsifying Drug Delivery Systems as a Novel Approach to the Management of Uncomplicated Malaria

“…Indeed, treatment failure has been associated with incomplete drug absorption [39,40]. In addition, a "fatty meal" is predominantly required to invoke the "food effect" [39,[41][42][43][44]. This "food effect" may enhance the absorption of co-administered lipophilic drugs (Section 3.2) due to the stimulation of bile secretion from the gallbladder, which in turn establishes a solubilising milieu of acid and homogenised fat to stimulate dietary lipid absorption [45].…”

“…However, as stated, it seems that incipient drug resistance is not the main concern, but rather under-dosing occurrences [54]. This is due to the inability to effectively deliver highly lipophilic treatment regimens (i.e., varied and/or limited drug absorption), thus needing a fatty meal in order to achieve adequate therapeutic drug levels in patients too nauseous to eat, for a period long enough to attain full recovery [44]. It is furthermore very difficult for patients residing in a third world country, that are not only constantly nauseous, but who live in poverty-stricken areas and do not have the means to obtain proper nutrition [182].…”

“…Currently, most novel drugs synthesised are similar to artemether and lumefantrine, i.e., highly lipophilic in nature and displaying poor aqueous solubility, highlighting the predicament we are in [189]. Thus, poor bioavailability, inadequate therapeutic drug-blood levels, poor water solubility, patient noncompliance and often the short half-lives of orally administered drugs have driven researchers to rather advance drug delivery systems that are able to improve the therapeutic efficacy of these types of drugs [39,40,44,190].…”