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Background Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine. Methods Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters. Results Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22–98) of mosquitoes positive for oocysts and 57% (range, 4–92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16–46) and 52% (IQR: 40–62), respectively, and by day 7, 81% (IQR 36–92) and 77% (IQR 52–98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified. Conclusions Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect. [ABSTRACT FROM AUTHOR]

Malaria remains a major public health burden in South-East Asia and Africa. Mathematical models of within-host infection dynamics and drug action, developed in support of malaria elimination initiatives, have significantly advanced our understanding of the dynamics of infection and supported development of effective drug-treatment regimens. However, the mathematical models supporting these initiatives are predominately based on deterministic dynamics and therefore cannot capture stochastic phenomena such as extinction (no parasitized red blood cells) following treatment, with potential consequences for our interpretation of data sets in which recrudescence is observed. Here we develop a stochastic within-host infection model to study the growth, decline and possible stochastic extinction of parasitized red blood cells in malaria-infected human volunteers. We show that stochastic extinction can occur when the inoculation size is small or when the number of parasitized red blood cells reduces significantly after an antimalarial treatment. We further show that the drug related parameters, such as the maximum killing rate and half-maximum effective concentration, are the primary factors determining the probability of stochastic extinction following treatment, highlighting the importance of highly-efficacious antimalarials in increasing the probability of cure for the treatment of malaria patients. [ABSTRACT FROM AUTHOR]

• A volunteer infection study to characterise the antimalarial pyronaridine. • Single doses (360–720 mg) exhibited potent Plasmodium falciparum blood-stage activity. • A pharmacokinetic/pharmacodynamic model was developed. • Results will support the development of new pyronaridine combination therapies. With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum -infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1–2 h, the elimination half-life was 8–9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC 90 : 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations. [Display omitted] [ABSTRACT FROM AUTHOR]

Malaria remains a major public health burden in South-East Asia and Africa. Mathematical models of within-host infection dynamics and drug action, developed in support of malaria elimination initiatives, have significantly advanced our understanding of the dynamics of infection and supported development of effective drug-treatment regimens. However, the mathematical models supporting these initiatives are predominately based on deterministic dynamics and therefore cannot capture stochastic phenomena such as extinction (no parasitized red blood cells) following treatment, with potential consequences for our interpretation of data sets in which recrudescence is observed. Here we develop a stochastic within-host infection model to study the growth, decline and possible stochastic extinction of parasitized red blood cells in malaria-infected human volunteers. We show that stochastic extinction can occur when the inoculation size is small or when the number of parasitized red blood cells reduces significantly after an antimalarial treatment. We further show that the drug related parameters, such as the maximum killing rate and half-maximum effective concentration, are the primary factors determining the probability of stochastic extinction following treatment, highlighting the importance of highly-efficacious antimalarials in increasing the probability of cure for the treatment of malaria patients.

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the Plasmodium falciparum induced blood-stage malaria (IBSM) model. Due to the high pharmacokinetic variability with the powder-in-bottle formulation used in both of these studies, a third study was undertaken to select a tablet formulation of MMV390048 to take forward into future studies. MMV390048 was generally well tolerated when administered as a single oral dose up to 120 mg, with rapid absorption and a long elimination half-life. Twelve adverse events were considered to be potentially related to MMV390048 in the first-in-human study but with no obvious correlation between these and MMV390048 dose or exposure. Although antimalarial activity was evident in the IBSM study, rapid recrudescence occurred in most subjects after treatment with 20 mg MMV390048, a dose expected to be subtherapeutic. Reformulation of MMV390048 into two tablet formulations (tartaric acid and Syloid) resulted in significantly reduced intersubject pharmacokinetic variability. Overall, the results of this study suggest that MMV390048 is well tolerated in humans, and the pharmacokinetic properties of the compound indicate that it has the potential to be used for antimalarial prophylaxis or inclusion in a single-dose cure. MMV390048 is currently being tested in a phase 2a study in Ethiopian adults with acute, uncomplicated falciparum or vivax malaria monoinfection. (The three clinical trials described here were each registered with ClinicalTrials.gov as follows: first-in-human study, registration no. NCT02230579; IBSM study, registration no. NCT02281344; and formulation optimization study, registration no. NCT02554799.)., (Copyright © 2020 Sinxadi et al.)

Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum -induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 ( n  = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 ( n  = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log 10 parasite reduction ratios over 48 h [PRR 48 ] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.)., (Copyright © 2019 McCarthy et al.)