Background Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria. Methods and findings We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ARTS infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum. Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3-8 days after dosing, and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single sub-therapeutic dose cohort, a minimum inhibitory concentration of 11.6 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/mL was estimated, and a single 95 mg dose (95% CI: 50-270) was predicted to clear 109 parasites/mL. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of cipargamin as a new treatment for P. falciparum malaria, although the hepatic safety profile of the compound warrants further evaluation.

Background Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate. Methods Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility. Results Initial parasite clearance occurred in all participants after artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11–14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4–8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. Conclusions The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria. Clinical Trials Registration NCT02573857.

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Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with bloodstage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour −1 (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing. Globally, 225 million cases of malaria have been reported with 7.5 million cases due to Plasmodium vivax. 1 Malaria causes an estimated 405,000 deaths worldwide in which 67% involve children aged under 5 years. 1 Chloroquine was the cornerstone of malaria treatment but the spread of drug resistance has rendered chloroquine ineffective for the treatment of P. falciparum malaria in almost all

Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48±2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60 kg adult. Conclusions Although a single dose of tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.

The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II studies between 1 January 2016 and 28 April 2021. PubMed, Web of Science, Embase, clinical trial registries and reference lists were searched for relevant studies. Information regarding antimalarial compound details, clinical trial characteristics, study population, drug pharmacokinetics and pharmacodynamics (PK-PD) were extracted. A total of 50 studies were included of which 24 had published their results and 26 were unpublished. New antimalarial compounds were evaluated as monotherapy (28 studies, 14 drug candidates) and combination therapy (9 studies, 10 candidates). Fourteen active compounds were identified in the current antimalarial drug development pipeline together with 11 compounds that are inactive; six due to insufficient efficacy. PK-PD data were available from 24 studies published as open-access articles. Four unpublished studies have made their results publicly available on clinical trial registries. The terminal elimination half-life of new antimalarial compounds ranged from 14.7 to 483 hours. The log 10 parasite reduction ratio over 48 hours and parasite clearance half-life for P. falciparum following a single dose monotherapy were 1.55–4.1 and 3.4–9.4 hours, respectively. The antimalarial drug development landscape has seen a number of novel compounds, with promising PK-PD properties, evaluated in phase I and II studies over the past 5 years. Timely public disclosure of PK-PD data is crucial for informative decision-making and drug development strategy.

Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. Conclusions Although a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.