Defining the effectiveness of antimalarial chemotherapy: Investigation of the lag in parasite clearance following drug administration

Background. The emergence of drug-resistant malaria highlights the need for new agents. A desired characteristic of candidate antimalarials is rapid killing of parasites. This is typically measured by the rate of exponential clearance of parasitemia following treatment. However, this clearance rate excludes the highly variable lag phase, when the parasitemia level may increase, remain constant, or decrease. Understanding factors determining this lag phase is important for drug development. Methods. We assessed the kinetics of parasitemia in 112 volunteers infected with blood-stage Plasmodium falciparum and treated with 8 different antimalarials. The parasitemia level was measured by quantitative polymerase chain reaction. We analyzed the relationship between the timing of treatment in the parasite growth cycle, and whether the parasitemia level rose or fell in the first 12 or 24 hours after treatment. Results. The timing of treatment in the parasite life cycle predicted whether subjects experienced rises or falls in parasitemia level after treatment. Antimalarials were unable to prevent rises in the parasitemia level in the first 12 hours. However, in the first 24 hours after treatment, fast-acting but not slow-acting drugs reduced the parasitemia level independent of when treatment was administered. Conclusions. The highly variable lag phase depends on the speed of action of an antimalarial and when in the periodic growth cycle it is administered

Model-informed drug development for malaria therapeutics.

Malaria is a critical public health problem resulting in substantial morbidity and mortality, particularly in developing countries. Owing to the development of resistance toward current therapies, novel approaches to accelerate the development efforts of new malaria therapeutics are urgently needed. There have been significant advancements in the development of in vitro and in vivo experiments that generate data used to inform decisions about the potential merit of new compounds. A comprehensive disease-drug model capable of integrating discrete data from different preclinical and clinical components would be a valuable tool across all stages of drug development. This could have an enormous impact on the otherwise slow and resource-intensive process of traditional clinical drug development

Model-informed drug development for malaria therapeutics.

Malaria is a critical public health problem resulting in substantial morbidity and mortality, particularly in developing countries. Owing to the development of resistance toward current therapies, novel approaches to accelerate the development efforts of new malaria therapeutics are urgently needed. There have been significant advancements in the development of in vitro and in vivo experiments that generate data used to inform decisions about the potential merit of new compounds. A comprehensive disease-drug model capable of integrating discrete data from different preclinical and clinical components would be a valuable tool across all stages of drug development. This could have an enormous impact on the otherwise slow and resource-intensive process of traditional clinical drug development

Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial.

Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria.This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966.Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3).Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs.Bill and Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development

Potent ex vivo activity of naphthoquine and methylene blue against drug-resistant clinical isolates of Plasmodium falciparum and Plasmodium vivax

The 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potent in vitro efficacies against Plasmodium falciparum, but susceptibility data for P. vivax are limited. The species- and stage-specific ex vivo activities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistant P. falciparum and P. vivax are prevalent. Both compounds were highly active against P. falciparum (median [range] 50% inhibitory concentration [IC50]: NQ, 8.0 nM [2.6 to 71.8 nM]; and MB, 1.6 nM [0.2 to 7.0 nM]) and P. vivax (NQ, 7.8 nM [1.5 to 34.2 nM]; and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC50s in parasites exposed at the trophozoite stage than at the ring stage for NQ in P. falciparum (26.5 versus 5.1 nM, P = 0.021) and P. vivax (341.6 versus 6.5 nM, P = 0.021) and for MB in P. vivax (10.1 versus 1.6 nM, P = 0.010). The excellent ex vivo activities of NQ and MB against both P. falciparum and P. vivax highlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic

Performance of BinaxNOW G6PD deficiency point-of-care diagnostic in P. vivax-infected subjects.

Accurate diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is required to avoid the risk of acute hemolysis associated with 8-aminoquinoline treatment. The performance of the BinaxNOW G6PD test compared with the quantitative spectrophotometric analysis of G6PD activity was assessed in 356 Plasmodium vivax-infected subjects in Brazil, Peru, Thailand, and India. In the quantitative assay, the median G6PD activity was 8.81 U/g hemoglobin (range = 0.05-20.19), with 11 (3%) subjects identified as deficient. Sensitivity of the BinaxNOW G6PD to detect deficient subjects was 54.5% (6 of 11), and specificity was 100% (345 of 345). Room temperatures inadvertently falling outside the range required to perform the rapid test (18-25°C) together with subtlety of color change and insufficient training could partially explain the low sensitivity found. Ensuring safe use of 8-aminoquinolines depends on additional development of simple, highly sensitive G6PD deficiency diagnostic tests suitable for routine use in malaria-endemic areas