Meningeal Inflammation Increases Artemether Concentrations in Cerebrospinal Fluid in Papua New Guinean Children Treated with Intramuscular Artemether

The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC 50 ) of 2.9 M. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 M, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC 50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.

Section: Discussionmentioning

confidence: 99%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

“…The concentration of ART in plasma was analyzed using liquid chromatography with mass spectrometry detection (LC-MS) based on an established assay for artemether (36). Stock solutions of ART and artemether (the internal standard) were prepared separately (1 g/liter in methanol) and were stored in the dark at Ϫ80°C.…”

Section: Methodsmentioning

confidence: 99%

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

Batty

Salman

Moore

et al. 2012

Self Cite

g Artemisinin-naphthoquine (ART-NQ) is a coformulated antimalarial therapy marketed as a single-dose treatment in Papua NewGuinea and other tropical countries. To build on limited knowledge of the pharmacokinetic properties of the components, especially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with uncomplicated malaria, comparing a single dose (15 and 6 mg/kg of body weight) administered with water (group 1; n ‫؍‬ 13), a single dose (22 and 9 mg/kg) with milk (group 2) (n ‫؍‬ 17), and two daily doses of 22 and 9 mg/kg with water (group 3; n ‫؍‬ 16). The plasma NQ concentration was assayed by high-performance liquid chromatography, and the plasma ART concentration was assayed using liquid chromatography-mass spectrometry. Population-based multicompartment pharmacokinetic models for NQ and ART were developed. NQ disposition was best characterized by a three-compartment model with a mean absorption half-life (t 1/2 ) of 1.0 h and predicted median maximum plasma concentrations that ranged as high as 57 g/liter after the second dose in group 3. The mean NQ elimination t 1/2 was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (V ss /F) was 710 liters/kg. Administration of NQ with fat (8.5 g; 615 kJ) versus water was associated with 25% increased bioavailability. ART disposition was best characterized by a two-compartment model with a mean CL/F (4.1 liters/h/kg) and V/F (21 liters/kg) similar to those of previous studies. There was a 77% reduction in the bioavailability of the second ART dose (group 3). NQ has pharmacokinetic properties that confirm its potential as an artemisinin partner drug for treatment of uncomplicated pediatric malaria.A vailable data relating to the pharmacokinetics of the antimalarial drug naphthoquine phosphate (NQ) are limited and inconsistent. Initial reports suggested that NQ has a high oral bioavailability (Ͼ90%) and a half-life (t 1/2 ) of 41 to 57 h (50). In a more recent study with healthy Chinese men in which NQ was given alone or coformulated with artemisinin (ART) (41), the elimination t 1/2 of NQ was substantially longer, at 250 to 300 h. This volunteer study also showed that the area under the concentration-time curve (AUC) for NQ exhibited an unusual relationship between the formulation and coadministered fat. The mean values were similar for the fasted group receiving NQ monotherapy and the fed group receiving combination ART-NQ therapy but more than double this for the fasted volunteers given the fixed combination (41). The fact that the highest bioavailability was in the fasting state appears in contrast to the effect of fat on the absorption of related drugs, such as lumefantrine and piperaquine (3,11,24,46), while the apparently beneficial effects of coformulation on bioavailability were difficult to explain (41).It has been shown that NQ is a P-glycoprotein substrate and that NQ efflux is saturable (12), suggesting that absorp...

“…There were 237 individual plasma DHA concentrations available for analysis, of which 43 (18.1%) were BLQ. As these represented a significant proportion of the data, a method previously described, namely, M3 (31), and successfully utilized in the PK analysis of antimalarial drugs (25,32) was employed. Initial modeling of the DHA data set demonstrated that a two-compartment model was not significantly better than a one-compartment model (⌬OFV ϭ Ϫ6.171, P ϭ 0.023, degrees of freedom [df] ϭ 2) and that the absorption phase was best de- scribed by a first-order absorption with a lag time.…”

Section: Safety and Tolerability (I) Adverse Events And Symptomsmentioning

confidence: 99%

Effect of Coadministered Fat on the Tolerability, Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

Moore

Benjamin

Salman

et al. 2014

g Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n ‫؍‬ 14, group A) or milk (n ‫؍‬ 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC 0 -ؕ ) for PQ (median, 41,906 versus 36,752 g · h/liter in groups A and B, respectively; P ‫؍‬ 0.24) or DHA (4,047 versus 4,190 g · h/liter; P ‫؍‬ 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QT c ) initially during follow-up, but the QT c tended to be higher in group B children at 24 h (mean ؎ standard deviation [SD], 15 ؎ 10 versus 6 ؎ 15 ms 0.5 in group A, P ‫؍‬ 0.067) and 168 h (10 ؎ 18 versus 1 ؎ 23 ms 0.5 , P ‫؍‬ 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded. Dihydroartemisinin-piperaquine (DHA-PQ) is a widely used artemisinin combination therapy (ACT) that has proved highly effective in a range of studies of children and adults with uncomplicated falciparum or vivax malaria (1). However, in a recent large-scale multiarm randomized trial in Papua New Guinean (PNG) children (2), DHA-PQ proved inferior to artemetherlumefantrine for treatment of Plasmodium falciparum infections and was associated with a treatment failure rate above that required by WHO for the adoption of a new antimalarial therapy (3). Among possible explanations for this unexpected result was the fact that the PNG children allocated to receive DHA-PQ took their tablets with water rather than in the fed state, potentially reducing bioavailability (4). Such an effect could be especially important in young children since conventional mg/kg body weight dosing gives rise to relatively low plasma PQ concentrations in this age group (5, 6).Evidence that PQ absorption is proportional to the amount of coadministered fat comes from a variety of studies in healthy adults and adults with uncomplicated malaria. A high-fat meal (typically containing around 50 g fat) is associated with at least a doubling of area under the PQ plasma concentrati...