Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Pharmacokinetic Study

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gQuantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/l for artemether-lumefantrine and 61/l for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/l (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia. Intraerythrocytic development of Plasmodium spp. comprises asexual reproduction, which underlies host pathophysiology or sexual reproduction (gametocyte formation) that is essential for malaria transmission. Apart from distinctive morphology, gametocytes have many characteristics that set them apart from asexual stages. Plasmodium falciparum gametocytes have a much longer life span in the circulation and, through metabolic inactivity during the mature phase, reduced antimalarial drug sensitivity (1-3). Artemisinin drugs have greater gametocytocidal activity than conventional agents, such as chloroquine, sulfadoxine, and pyrimethamine, in P. falciparum infections (4-7). As their half-lives are relatively short, this greater potency arises largely from their ability to destroy a wider range of early-stage gametocytes, presumably at their sequestration sites (4, 8). However, the exact effect of antimalarial drugs on the viability of more mature P. falciparum gametocytes that continue to circulate after treatment is unc...

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Karl

Laman

Moore

et al. 2015

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“…In a pharmacokinetic study of uncomplicated malaria in children in which a two-compartment model was used, the artemether elimination t 1/2 was similarly long (Ն23 h) (23). This second (terminal) elimination phase contributes Ͻ20% to the AUC in the present studies and may reflect the combination of a long duration of sampling postdose and a relatively sensitive assay, as we have found with artemisinin itself (30).…”

Section: Figmentioning

confidence: 74%

“…This may reflect the fact that the plasma concentrations achieved in the present study were, consistent with the dose administered, less than those in previous studies (25,28), with the possibility that higher con- centrations have a greater effect on autoinduction. However, given that artemether autoinduction is slower and less marked than that associated with artemisinin itself (30) and that ArTiMist as monotherapy should not be given for more than a few doses with a likely role in prereferral treatment, this phenomenon appears to be of limited clinical relevance. The doses used in the present study were the lowest in all published pharmacokinetic studies of artemether in healthy volunteers, specifically, Յ0.6 mg/kg of body weight versus 1.6 to 9.6 mg/kg of body weight, respectively (10,11,13,15,25).…”

Section: Discussionmentioning

confidence: 88%

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

Salman

Bendel²,

Lee

et al. 2015

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Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (>1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (>1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.

“…Group 1 patients had additional venous blood samples drawn through the cannula at 1, 2, 4, 8, 12, 18, 24, 48, and 72 h and by venesection at 4, 7, 14, 28, 42, and 56 days for subsequent drug assay (1). These children were reassessed clinically at 4 and 24 h and on days 2, 3, 7, 14, 28, 42, and 56.…”

Section: Methodsmentioning

confidence: 99%

Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Tolerability, Safety, and Preliminary Efficacy Study

Benjamin

Moore

Lee

et al. 2012

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dArtemisinin-naphthoquine (ART-NQ) is a fixed-dose coformulated antimalarial therapy recommended as a single-dose treatment and marketed in Papua New Guinea among other tropical countries. We conducted a tolerability, safety, and efficacy study of ART-NQ for Papua New Guinean children aged 5 to 12 years with uncomplicated malaria, comparing single-dose ART-NQ (15 and 6 mg/kg of body weight) given with water (group 1; n ‫؍‬ 15), single-dose ART-NQ (22 and 9 mg/kg) given with milk (group 2; n ‫؍‬ 17), or two daily doses of 22 and 9 mg/kg given with water (group 3; n ‫؍‬ 16). Of the 48 children (45 with Plasmodium falciparum malaria, 2 with Plasmodium vivax malaria, and 1 with mixed-species malaria), 2 in group 2 did not attend all follow-up assessments. All regimens were well tolerated, with no serious adverse events. There were no clinically significant changes in pulse, blood pressure, rate-corrected electrocardiographic QT, routine biochemistry/hematology, or hearing after treatment. Fever clearance was prompt. Mean 50% parasite clearance times were 4, 4, and 5 h for groups 1, 2, and 3, respectively. One group 1 patient had PCR-confirmed P. falciparum recrudescence at day 23; four had PCR-confirmed P. falciparum reinfections on day 28 or 42; and three had P. vivax infections detected on day 42. The only recurrent parasitemia in groups 2 and 3 occurred in a group 2 child who developed a P. vivax infection on day 42. Day 14 gametocyte positivity levels were 20%, 27%, and 9% in groups 1, 2, and 3, respectively. The lower single ART-NQ dose was associated with relatively frequent recurrence of parasitemia, but the prolonged gametocytemia in all three groups has implications for the transmission of malaria.