Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

Abstract

A lthough parenteral artesunate is the recommended initial treatment for severe malaria (1), intramuscular (i.m.) artemether is an acceptable and practical alternative (1, 2). Artemether is also a recommended first-line oral therapy in combination with the longer half-life partner drug lumefantrine for uncomplicated Plasmodium falciparum (3) and Plasmodium vivax (4) infections. There are, however, few detailed studies assessing the pharmacokinetics of artemether and its active metabolite dihydroartemisinin (DHA) in either of these settings in children.Artemether-lumefantrine is a safe and effective treatment for uncomplicated pediatric malaria (3, 4), but there is evidence of significant between-dose variability in absorption even when coadministered with a small amount of fat to improve bioavailability (5). In addition, the nausea and vomiting that are frequently associated with malaria, together with an unwell child's refusal to feed or take medications by mouth (6), can reduce the effectiveness of oral treatment through reduced adherence to the World Health Organization (WHO) recommended 3-day regimen (7). In cases of more severe malaria, there is evidence of substantial between-patient variability in the absorption of i.m. artemether (8, 9), with some acidotic children likely exposed to subtherapeutic concentrations when the recommended doses are given (9). Rectal artesunate administration is associated with more rapid absorption and initial parasite clearance than is i.m. artemether administration in severely ill children (8). However, there is also marked between-patient variability in the dispositions of artesunate and DHA, and there is evidence that some children are able to expel artesunate suppositories even in the context of close monitoring as part of a formal pharmacokinetic evaluation (10). This might help explain why artesunate suppositories do not improve mortality compared to that with a placebo in older relative to younger pediatric age groups (11).There is a clear need for a prereferral formulation of an artemisinin derivative that can be easily administered and adequately absorbed in a child who may be unconscious or uncooperative or in whom nausea and vomiting preclude oral dosing. ArTiMist (Essential Nutrition Ltd., Brough, England) is an artemether formulation in neutral oil that can be administered as a metered sublingual spray and which is more rapidly and completely absorbed than is artemether given in tablet form in healthy adult volunteers (see accompanying paper [12]). In the present study, we assessed the pharmacokinetics of ArTiMist in African children with severe malaria or in whom gastrointestinal symptoms prevented the administration of artemether-lumefantrine tablets.

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

“…This notion has been challenged by a report indicating that NALT DCs possess the machinery for induction of RA and expression of α4β7+ on effector B cells, but stimulation by microbiota was required for these functions to develop (46). The sublingual route is used effectively for delivery of medication and allergen-specific immune therapy in humans and animals (47–50). This route has recently emerged as a mode of vaccine delivery capable of eliciting both systemic and mucosal immune responses while avoiding many of the side effects and formulation concerns associated with oral or intranasal vaccination (51–53).…”

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

“…In addition, the nausea and vomiting associated with a febrile illness, such as malaria, which can be exacerbated by oral dosing with fluids or food, are less of a barrier to treatment with sublingual administration. ArTiMist (Essential Nutrition Ltd., Brough, England) is a sublingual formulation of artemether in neutral oil that is administered as a metered sublingual spray and which is being developed as a candidate for prereferral treatment, especially in young children (see the accompanying paper [19]). In the present study, the first of two pharmacokinetic evaluations of this product, the disposition of ArTiMist relative to that of single-dose oral artemether given as tablets, as well as its multidose pharmacokinetics, were examined in healthy adult volunteers.…”

Efficacy of a Novel Sublingual Spray Formulation of Artemether in African Children with Plasmodium falciparum Malaria

“…The present study was conducted in two parts. Study (10,11). The present paper provides details of the trial procedures and efficacy and safety outcomes.…”

“…Pharmacokinetic analysis shows that ArTiMist is promptly and adequately absorbed regardless of the indices of severity, including consciousness level, and even in patients with a history of vomiting at presentation (11). Simulations demonstrated that sublingual artemether bioavailability (artemether and dihydroartemisinin [DHA]) was at least equivalent to that after conventional artemether-lumefantrine oral therapy in older Melanesian children with uncomplicated malaria (11).…”

“…Simulations demonstrated that sublingual artemether bioavailability (artemether and dihydroartemisinin [DHA]) was at least equivalent to that after conventional artemether-lumefantrine oral therapy in older Melanesian children with uncomplicated malaria (11).…”