ABSTRACT
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 adults with normal levels of G6PD 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 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, 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. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).
Subject(s)
Antimalarials , Malaria, Falciparum , Adult , Humans , Antimalarials/adverse effects , Plasmodium falciparum , Healthy Volunteers , Parasitemia/drug therapy , Artemether/pharmacology , Artemether/therapeutic use , Artemether, Lumefantrine Drug Combination/therapeutic use , Australia , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitologyABSTRACT
The development of new combinations of antimalarial drugs is urgently needed to prevent the spread of parasites resistant to drugs in clinical use and contribute to the control and eradication of malaria. In this work, we evaluated a standardized humanized mouse model of erythrocyte asexual stages of Plasmodium falciparum (PfalcHuMouse) for the selection of optimal drug combinations. First, we showed that the replication of P. falciparum was robust and highly reproducible in the PfalcHuMouse model by retrospective analysis of historical data. Second, we compared the relative value of parasite clearance from blood, parasite regrowth after suboptimal treatment (recrudescence), and cure as variables of therapeutic response to measure the contributions of partner drugs to combinations in vivo. To address the comparison, we first formalized and validated the day of recrudescence (DoR) as a new variable and found that there was a log-linear relationship with the number of viable parasites per mouse. Then, using historical data on monotherapy and two small cohorts of PfalcHuMice evaluated with ferroquine plus artefenomel or piperaquine plus artefenomel, we found that only measurements of parasite killing (i.e., cure of mice) as a function of drug exposure in blood allowed direct estimation of the individual drug contribution to efficacy by using multivariate statistical modeling and intuitive graphic displays. Overall, the analysis of parasite killing in the PfalcHuMouse model is a unique and robust experimental in vivo tool to inform the selection of optimal combinations by pharmacometric pharmacokinetic and pharmacodynamic (PK/PD) modeling.
Subject(s)
Antimalarials , Malaria, Falciparum , Animals , Mice , Antimalarials/pharmacology , Antimalarials/therapeutic use , Plasmodium falciparum , Retrospective Studies , Peroxides , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Drug CombinationsABSTRACT
BACKGROUND: The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. OBJECTIVES: This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model. METHODS: A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite's life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework. RESULTS: The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration. CONCLUSIONS: Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.
Subject(s)
Antimalarials , Malaria, Falciparum , Malaria , Pyrimidines/pharmacokinetics , Triazoles/pharmacokinetics , Antimalarials/therapeutic use , Bayes Theorem , Dose-Response Relationship, Drug , Drug Therapy, Combination , Humans , Malaria/drug therapy , Malaria, Falciparum/drug therapy , Plasmodium falciparumABSTRACT
BACKGROUND: Malaria-associated anaemia, arising from symptomatic, asymptomatic and submicroscopic infections, is a significant cause of morbidity worldwide. Induced blood stage malaria volunteer infection studies (IBSM-VIS) provide a unique opportunity to evaluate the haematological response to early Plasmodium falciparum and Plasmodium vivax infection. METHODS: This study was an analysis of the haemoglobin, red cell counts, and parasitaemia data from 315 participants enrolled in IBSM-VIS between 2012 and 2019, including 269 participants inoculated with the 3D7 strain of P. falciparum (Pf3D7), 15 with an artemisinin-resistant P. falciparum strain (PfK13) and 46 with P. vivax. Factors associated with the fractional fall in haemoglobin (Hb-FF) were evaluated, and the malaria-attributable erythrocyte loss after accounting for phlebotomy-related losses was estimated. The relative contribution of parasitized erythrocytes to the malaria-attributable erythrocyte loss was also estimated. RESULTS: The median peak parasitaemia prior to treatment was 10,277 parasites/ml (IQR 3566-27,815), 71,427 parasites/ml [IQR 33,236-180,213], and 34,840 parasites/ml (IQR 13,302-77,064) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. The median Hb-FF was 10.3% (IQR 7.8-13.3), 14.8% (IQR 11.8-15.9) and 11.7% (IQR 8.9-14.5) in those inoculated with Pf3D7, PfK13 and P. vivax, respectively, with the haemoglobin nadir occurring a median 12 (IQR 5-21), 15 (IQR 7-22), and 8 (IQR 7-15) days following inoculation. In participants inoculated with P. falciparum, recrudescence was associated with a greater Hb-FF, while in those with P. vivax, the Hb-FF was associated with a higher pre-treatment parasitaemia and later day of anti-malarial treatment. After accounting for phlebotomy-related blood losses, the estimated Hb-FF was 4.1% (IQR 3.1-5.3), 7.2% (IQR 5.8-7.8), and 4.9% (IQR 3.7-6.1) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. Parasitized erythrocytes were estimated to account for 0.015% (IQR 0.006-0.06), 0.128% (IQR 0.068-0.616) and 0.022% (IQR 0.008-0.082) of the malaria-attributable erythrocyte loss in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. CONCLUSION: Early experimental P. falciparum and P. vivax infection resulted in a small but significant fall in haemoglobin despite parasitaemia only just at the level of microscopic detection. Loss of parasitized erythrocytes accounted for < 0.2% of the total malaria-attributable haemoglobin loss.
Subject(s)
Anemia/drug therapy , Antimalarials/therapeutic use , Erythrocytes/parasitology , Malaria, Falciparum/drug therapy , Malaria, Vivax/drug therapy , Parasitemia/drug therapy , Adult , Anemia/parasitology , Female , Humans , Malaria, Falciparum/complications , Malaria, Falciparum/parasitology , Malaria, Vivax/complications , Malaria, Vivax/parasitology , Male , Middle Aged , Parasitemia/parasitology , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Young AdultABSTRACT
BACKGROUND: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. METHODS: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. RESULTS: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5-64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5-15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61-4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16-4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. CONCLUSION: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134.
Subject(s)
Antimalarials/therapeutic use , Biological Specimen Banks , Clinical Trials as Topic , Healthy Volunteers/statistics & numerical data , Malaria, Falciparum/drug therapy , Plasmodium falciparumABSTRACT
BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. RESULTS: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
Subject(s)
Antimalarials/metabolism , Antimalarials/pharmacology , Drug Development , Drug Discovery , Antimalarials/blood , Antimalarials/standards , Caco-2 Cells , Chromatography, Liquid , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Humans , Kinetics , Microsomes, Liver , Permeability , Protein Binding , Solubility , Tandem Mass SpectrometryABSTRACT
BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.
Subject(s)
Acrylamides/pharmacology , Antimalarials/pharmacology , Piperazines/pharmacology , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Acrylamides/pharmacokinetics , Animals , Antimalarials/pharmacokinetics , Artemisinins/pharmacology , Dose-Response Relationship, Drug , Female , Humans , Mice , Mice, Inbred NOD , Microbial Sensitivity Tests , Multidrug Resistance-Associated Proteins/metabolism , Piperazines/pharmacokinetics , Plasmodium berghei/drug effectsABSTRACT
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 (MPC90: 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.
Subject(s)
Antimalarials , Healthy Volunteers , Malaria, Falciparum , Naphthyridines , Parasitemia , Plasmodium falciparum , Humans , Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Antimalarials/pharmacology , Antimalarials/administration & dosage , Naphthyridines/pharmacokinetics , Naphthyridines/therapeutic use , Naphthyridines/pharmacology , Naphthyridines/administration & dosage , Plasmodium falciparum/drug effects , Adult , Male , Young Adult , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Female , Parasitemia/drug therapy , Parasitemia/parasitology , Erythrocytes/drug effects , Erythrocytes/parasitology , Administration, Oral , Middle Aged , Treatment OutcomeABSTRACT
AIMS: To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. METHODS: OZ439 was administered as single oral daily doses of a capsule formulation (50-1200 mg) or an oral dispersion (400-1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800 mg day(-1)). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. RESULTS: The pharmacokinetic (PK) profile of OZ439 was characterized by a t(max) of around 3 h, followed by a multiphasic profile with a terminal half-life of 25-30 h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t(1/2) of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites. CONCLUSION: The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.
Subject(s)
Adamantane/analogs & derivatives , Antimalarials/adverse effects , Antimalarials/pharmacokinetics , Peroxides/adverse effects , Peroxides/pharmacokinetics , Adamantane/adverse effects , Adamantane/pharmacokinetics , Administration, Oral , Adolescent , Adult , Area Under Curve , Chromatography, Liquid , Dose-Response Relationship, Drug , Double-Blind Method , Fasting , Female , Food-Drug Interactions , Half-Life , Humans , Male , Mass Spectrometry , Middle Aged , Young AdultABSTRACT
Over the past decade, there has been a transformation in the portfolio of medicines to combat malaria. New fixed-dose artemisinin combination therapy is available, with four different types having received approval from Stringent Regulatory Authorities or the World Health Organization (WHO). However, there is still scope for improvement. The Malaria Eradication Research agenda identified several gaps in the current portfolio. Simpler regimens, such as a single-dose cure are needed, compared with the current three-day treatment. In addition, new medicines that prevent transmission and also relapse are needed, but with better safety profiles than current medicines. There is also a big opportunity for new medicines to prevent reinfection and to provide chemoprotection. This study reviews the global portfolio of new medicines in development against malaria, as of the summer of 2012. Cell-based phenotypic screening, and 'fast followers' of clinically validated classes, mean that there are now many new classes of molecules starting in clinical development, especially for the blood stages of malaria. There remain significant gaps for medicines blocking transmission, preventing relapse, and long-duration molecules for chemoprotection. The nascent pipeline of new medicines is significantly stronger than five years ago. However, there are still risks ahead in clinical development and sustainable funding of clinical studies is vital if this early promise is going to be delivered.
Subject(s)
Antimalarials/isolation & purification , Drug Discovery/trends , Malaria/drug therapy , Malaria/prevention & control , Antimalarials/pharmacology , HumansABSTRACT
Drug discovery for malaria has traditionally focused on orally available drugs that kill the abundant, parasitic blood stage. Recently, there has also been an interest in injectable medicines, in the form of monoclonal antibodies (mAbs) with long-lasting plasma half-lives or long-lasting depot formulations of small molecules. These could act as prophylactic drugs, targeting the sporozoites and other earlier parasitic stages in the liver, when the parasites are less numerous, or as another intervention strategy targeting the formation of infectious gametocytes. Generally speaking, the development of mAbs is less risky (costly) than small-molecule drugs, and they have an excellent safety profile with few or no off-target effects. Therefore, populations who are the most vulnerable to malaria, i.e., pregnant women and young children would have access to such new treatments much faster than is presently the case for new antimalarials. An analysis of mAbs that were successfully developed for oncology illustrates some of the feasibility aspects, and their potential as affordable drugs in low- and middle-income countries.
ABSTRACT
Malaria drug trials conducted in endemic areas face a major challenge in their analysis because it is difficult to establish whether parasitaemia in blood samples collected after treatment indicate drug failure or a new infection acquired after treatment. It is therefore vital to reliably distinguish drug failures from new infections in order to obtain accurate estimates of drug failure rates. This distinction can be achieved for Plasmodium falciparum by comparing parasite genotypes obtained at the time of treatment (the baseline) and on the day of recurring parasitaemia. Such PCR correction is required to obtain accurate failure rates, even for new effective drugs. Despite the routine use of PCR correction in surveillance of drug resistance and in clinical drug trials, limitations inherent to the molecular genotyping methods have led some researchers to question the validity of current PCR correction strategies. Here we describe and discuss recent developments in these genotyping approaches, with a particular focus on method validation and limitations of the genotyping strategies. Our aim is to update scientists from public and private bodies who are working on the development, deployment, and surveillance of new malaria drugs. We aim to promote discussion around these issues and argue for the adoption of improved standardised PCR correction methodologies.
Subject(s)
Antimalarials/therapeutic use , Clinical Trials as Topic , Genotyping Techniques/methods , Malaria, Falciparum/diagnosis , Malaria, Falciparum/drug therapy , Plasmodium falciparum/isolation & purification , Polymerase Chain Reaction/methods , Genotype , Humans , Plasmodium falciparum/classification , Plasmodium falciparum/genetics , Recurrence , Treatment OutcomeABSTRACT
Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days post-treatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; P = 0.02) for every log10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; P = 0.06), this risk disappeared when corrected for PCB. Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.
Subject(s)
Adamantane/analogs & derivatives , Alanine Transaminase/blood , Antimalarials/therapeutic use , Liver Diseases/drug therapy , Malaria, Vivax/drug therapy , Peroxides/therapeutic use , Plasmodium vivax/isolation & purification , Adamantane/therapeutic use , Adult , Artemisinins/therapeutic use , Chloroquine/therapeutic use , Cohort Studies , Female , Humans , Liver Diseases/blood , Liver Diseases/parasitology , Liver Function Tests , Malaria, Vivax/blood , Malaria, Vivax/parasitology , Malaysia , Male , Parasitemia/drug therapy , Thailand , Young AdultABSTRACT
BACKGROUNDInterventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naive individuals.METHODSHealthy, malaria-naive adults were enrolled in 2 studies to assess the safety, infectivity, and transmissibility of a new P. vivax isolate. Participants (Study 1, n = 2; Study 2, n = 24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes.RESULTSParasitemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Sixty-nine percent of participants (11/16) were infectious to Anopheles mosquitoes at peak gametocytemia. Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture.CONCLUSIONWe have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle.TRIAL REGISTRATIONACTRN12614000930684 and ACTRN12616000174482.FUNDING(Australian) National Health and Medical Research Council Program Grant 1132975 (Study 1). Bill and Melinda Gates Foundation (OPP1111147) (Study 2).
Subject(s)
Artemether, Lumefantrine Drug Combination/administration & dosage , Chloroquine/administration & dosage , Malaria, Vivax , Plasmodium vivax/metabolism , Adolescent , Adult , Animals , Anopheles , Female , Humans , Malaria, Vivax/drug therapy , Malaria, Vivax/metabolism , Malaria, Vivax/transmission , Male , Middle Aged , Models, Biological , Pilot ProjectsABSTRACT
INTRODUCTION: DSM421, a dihydroorotate dehydrogenase inhibitor, was in preclinical development as a potential treatment option for malaria. When tested in a core battery of safety pharmacology assays, DSM421 did not produce any effects at oral doses up to 750â¯mg/kg in an Irwin test in rats, but a respiratory study in rats using head-out plethysmography resulted in substantial changes in respiratory function as well as moribundity and mortality at that and lower doses. An investigation was performed to determine the source of this discrepancy. METHODS: Potential testing errors, differences in types of plethysmography testing chambers, effects on stress indicators, and off-target activity were investigated. RESULTS: Respiratory changes and toxicity (resulting in euthanasia in extremis) were confirmed in a repeat, head-out plethysmography test, but the effects of DSM421 were much less severe overall when the rats were tested in whole-body chambers. Additionally, at the end of the 5-h post-dosing respiratory monitoring periods, levels of stress-related hormones (particularly corticosterone) were higher overall in the head-out, than in the whole-body, tested rats. Furthermore, DSM421 was found to produce changes in cardiovascular function in unrestrained rats, and it was shown to have off-target binding affinity at the adenosine A3 receptor (which is associated with bronchoconstriction). DISCUSSION: The generalized stress inherent to head-out plethysmography testing exacerbated the respiratory effects of DSM421 and was possibly compounded by DSM421's cardiovascular effects, thus artifactually resulting in moribundity and mortality in rats. Care should be taken when choosing whether to use head-out versus whole-body plethysmography chambers during respiratory function testing in animals.
ABSTRACT
Piperaquine phosphate is an orally active bisquinolone antimalarial drug that has been used for the past 3 decades. The authors report the safety, tolerability, and pharmacokinetics of piperaquine from a classical controlled phase I study. It was a double-blind, randomized, parallel-group, placebo-controlled, and single- and multiple-dose study. During the rising single-dose study, single ascending oral doses of 500, 750, 1000, 1250, and 1500 mg of piperaquine phosphate were administered, whereas in rising multiple-dose study, once-daily ascending oral doses of 500, 750, 1000, and 1500 mg were administered for 3 consecutive days. Pharmacokinetic analysis for both the rising single- and multiple-dose studies was done using the noncompartmental approach. The mean apparent terminal half-life ranged from 11 to 23 days. Increase in exposure was less than dose proportional and linear. Piperaquine concentrations were measurable up to 60 days postdose. Multiple peaks were observed in the plasma piperaquine concentration-time profiles and exhibited 3- to 7-fold accumulation following multiple dosing. Piperaquine was well tolerated following single and multiple doses.
Subject(s)
Antimalarials/pharmacokinetics , Quinolines/pharmacokinetics , Administration, Oral , Adult , Antimalarials/administration & dosage , Antimalarials/adverse effects , Area Under Curve , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Headache/chemically induced , Humans , Male , Metabolic Clearance Rate , Middle Aged , Quinolines/adverse effects , Quinolines/blood , Tablets , Tandem Mass Spectrometry , Time Factors , Treatment Outcome , Vomiting/chemically inducedABSTRACT
Arterolane (RBx11160, OZ277) maleate is a rapidly acting synthetic trioxolane anti-malarial. This randomized, placebo controlled study was a phase I study to evaluate the clinical safety and tolerability as well as pharmacokinetics (PKs) of arterolane maleate including food effect. Eight single rising oral doses of arterolane (25, 50, 100, 150, 200, 300, 400, 600 mg), food effect under fed and fasting conditions at 100 mg dose and four multiple oral dose regimens (25, 50, 100, 200 mg) were administered once daily for 7 days in 64 healthy young males (Caucasian). A randomized, placebo-controlled study was also conducted in healthy elderly males and females (Caucasian) to investigate PKs, safety and tolerability of single oral dose (100 mg) of arterolane. All doses were well tolerated after oral administration. The initial peak of arterolane was apparent at 2-3 hours post-dose followed by a secondary peak at approximately 5 hours post-dose. Thereafter, plasma arterolane concentration declined with a geometric mean t1/2 of approximately 2-4 hours. The PKs of arterolane appeared to be time-invariant after repeated once-daily dosing. The incidence of adverse events was similar for placebo and active treatments. Arterolane had similar PKs and tolerability in elderly and younger subjects and between elderly males and females.
Subject(s)
Antimalarials , Heterocyclic Compounds, 1-Ring , Peroxides , Spiro Compounds , Administration, Oral , Adolescent , Adult , Aged , Antimalarials/administration & dosage , Antimalarials/adverse effects , Antimalarials/blood , Antimalarials/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Female , Food-Drug Interactions , Healthy Volunteers , Heterocyclic Compounds, 1-Ring/administration & dosage , Heterocyclic Compounds, 1-Ring/adverse effects , Heterocyclic Compounds, 1-Ring/blood , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Humans , Male , Middle Aged , Peroxides/administration & dosage , Peroxides/adverse effects , Peroxides/blood , Peroxides/pharmacokinetics , Spiro Compounds/administration & dosage , Spiro Compounds/adverse effects , Spiro Compounds/blood , Spiro Compounds/pharmacokinetics , Young AdultABSTRACT
Arterolane (RBx 11160) maleate is a novel, rapidly acting synthetic trioxolane antimalarial compound being developed by Ranbaxy Research Laboratories (Haryana, India). It is presently under phase III in combination with piperaquine phosphate. The present work reports the relationship between pharmacokinetic (PK) parameter (AUC(0-8h) on day 0/day 6) and indices of pharmacodynamic (PD) response (50% parasite clearance [PC(50)], 90% parasite clearance [PC(90)], parasite clearance time [PCT], recrudescence) from a phase II, double-blind, multicenter, randomized, parallel-group, dose-ranging trial. Patients with acute uncomplicated P. falciparum malaria were randomized to 1 of 3 arterolane maleate (50, 100, and 200 mg) doses for 7 consecutive days. Plasma concentration data were available from 78, 76, and 75 patients receiving a 50-, 100-, and 200-mg dose, respectively. Based on PD modeling, its limitations and assumptions, minimum 150-mg dose arterolane maleate was recommended to optimize the probability of maximum therapeutic benefits for an adult. Doses higher than 100 mg are unlikely to reduce the probability of recrudescence. This study re-stresses the need of combining short and long-acting drugs to prevent resistance development and minimize recrudescence.