The Experts below are selected from a list of 606 Experts worldwide ranked by ideXlab platform
Michael D. Edstein - One of the best experts on this subject based on the ideXlab platform.
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8-Aminoquinolines: Primaquine and Tafenoquine
Treatment and Prevention of Malaria, 2011Co-Authors: Norman C. Waters, Michael D. EdsteinAbstract:8-Aminoquinolines are an important class of antimalarial drugs because they are effective against the liver stages of Plasmodium infections and thus are administered for radical cure and presumptive antirelapse therapy against relapsing malaria. In this chapter, we discuss two 8-aminoquinolines, primaquine and Tafenoquine. Primaquine was identified in 1946 and has been used extensively to clear liver-stage parasites, especially those from Plasmodium vivax. These can persist in the liver for months, as a dormant form of the parasite (the hypnozoite), which re-emerges much later to cause clinical disease. Tafenoquine, a primaquine analog, is currently under advanced clinical development. Tafenoquine has a much longer elimination half-life compared with primaquine (14 days versus 6 h) and is highly effective both in treating relapses of P. vivax malaria and as a causal prophylactic agent against P. falciparum and P. vivax malaria. A major drawback to the 8-aminoquinolines is their toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. We discuss clinical uses, pharmacokinetics and metabolism, safety and tolerability, mechanisms of action and drug resistance for both these drugs.
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randomized double blind study of the safety tolerability and efficacy of Tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Peter Nasveld, Scott Kitchener, Michael D. Edstein, Mark Reid, Leonard Brennan, Ivor Harris, Peter A Leggat, Philip Pickford, Caron Kerr, Colin OhrtAbstract:This study represents the first phase III trial of the safety, tolerability, and effectiveness of Tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg Tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, Tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (Tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on Tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the Tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of Tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, Tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.
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population pharmacokinetics of Tafenoquine during malaria prophylaxis in healthy subjects
Antimicrobial Agents and Chemotherapy, 2007Co-Authors: B G Charles, Peter Nasveld, Mark Reid, Ivor Harris, Ann K Miller, Michael D. EdsteinAbstract:The population pharmacokinetics of Tafenoquine were studied in Australian soldiers taking Tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg Tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg Tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma Tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for Tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma Tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of Tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.
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Tafenoquine for the treatment of recurrent Plasmodium vivax malaria
American Journal of Tropical Medicine and Hygiene, 2007Co-Authors: Scott Kitchener, Peter Nasveld, Michael D. EdsteinAbstract:Tafenoquine was used to treat Plasmodium vivax malaria cases who had previously failed treatment with chloroquine and primaquine. Chloroquine was followed by a loading dose of Tafenoquine (200 mg base/day for 3 days) and 200 mg a week was given for 8 weeks. One of 27 treated patients relapsed after 6 months of observation. A standard course of chloroquine administered with 8 weeks of Tafenoquine may be more effective than chloroquine with primaquine (22.5 mg/day for 14 days) in preventing additional P. vivax relapses. Larger studies are required to optimize the combination, but our findings suggest that an extended use of Tafenoquine may be required to prevent relapses of primaquine-tolerant strains of P. vivax malaria.
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gender differences in gastrointestinal disturbances and plasma concentrations of Tafenoquine in healthy volunteers after Tafenoquine administration for post exposure vivax malaria prophylaxis
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2007Co-Authors: Michael D. Edstein, Peter Nasveld, Scott Kitchener, D A Kocisko, Michelle L Gatton, Karl H. RieckmannAbstract:In an open-label sequential cohort study, we compared gastrointestinal (GI) disturbances and plasma Tafenoquine concentrations after administration of single-dose (400 mg daily × 3 days; n = 76 males, 11 females) and split-dose (200 mg twice daily × 3 days; n = 73 males, 13 females) Tafenoquine regimens in healthy Australian Defence Force volunteers for post-exposure malaria prophylaxis. The female and male volunteers had comparable demographic characteristics (age, weight, height) in the single- and split-dose treatment groups. GI disturbances were generally mild and self-limiting for both groups. The frequency of nausea and abdominal distress was over two-fold higher in females than in males for both treatment groups. Reporting of GI disturbances in the single-dose group differed significantly between males and females, but this gender difference was not seen for the split-dose group. In those volunteers who experienced GI disturbances, the mean plasma Tafenoquine concentrations 12 h after the last dose of Tafenoquine were approximately 1.3-fold higher in females than in males (means ± SD: 737 ± 118 ng/ml vs. 581 ± 113 ng/ml). These preliminary findings suggest that further studies are required in a larger number of females to determine whether there is a need to reduce the dose of Tafenoquine to minimise GI disturbances in females.
Colin Ohrt - One of the best experts on this subject based on the ideXlab platform.
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comparative ophthalmic assessment of patients receiving Tafenoquine or chloroquine primaquine in a randomized clinical trial for plasmodium vivax malaria radical cure
International Ophthalmology, 2019Co-Authors: Sukhuma Warrasak, Srivicha Krudsood, Mark M Fukuda, Ataya Euswas, Mali Ittiverakul, Scott R Miller, Colin OhrtAbstract:Ophthalmic safety observations are reported from a clinical trial comparing Tafenoquine (TQ) efficacy and safety versus sequential chloroquine (CQ)/primaquine (PQ) for acute Plasmodium vivax malaria. In an active-control, double-blind study, 70 adult subjects with microscopically confirmed P. vivax malaria were randomized (2:1) to receive 400 mg TQ × 3 days or 1500 mg CQ × 3 days then 15 mg PQ × 14 days. Main outcome measures: clinically relevant changes at Day 28 and Day 90 versus baseline in the ocular examination, color vision evaluation, and corneal and retinal digital photography. Post-baseline keratopathy occurred in 14/44 (31.8%) patients with TQ and 0/24 with CQ/PQ (P = 0.002). Mild post-baseline retinal findings were reported in 10/44 (22.7%) patients receiving TQ and 2/24 (8.3%) receiving CQ/PQ (P = 0.15; treatment difference 14.4%, 95% CI − 5.7, 30.8). Masked evaluation of retinal photographs identified a retinal hemorrhage in one TQ patient (Day 90) and a slight increase in atrophy from baseline in one TQ and one CQ/PQ patient. Visual field sensitivity (Humphrey™ 10-2 test) was decreased in 7/44 (15.9%) patients receiving TQ and 3/24 (12.5%) receiving CQ/PQ; all cases were < 5 dB. There were no clinically relevant changes in visual acuity or macular function tests. There was no evidence of clinically relevant ocular toxicity with either treatment. Mild keratopathy was observed with TQ, without conclusive evidence of early retinal changes. Eye safety monitoring continues in therapeutic studies of low-dose Tafenoquine (300 mg single dose). Clinicaltrials.gov identifier: NCT01290601.
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Causal Prophylactic Efficacy of Primaquine, Tafenoquine, and Atovaquone-Proguanil Against Plasmodium cynomolgi in a Rhesus Monkey Model
The Journal of parasitology, 2014Co-Authors: Charles A. Ditusa, Rawiwan Im-erbsin, Anchalee Tungtaeng, Michael P. Kozar, Brandon S. Pybus, Jason Sousa, Judith Berman, Montip Gettayacamin, Colin OhrtAbstract:Abstract: Since the 1940s, the large animal model to assess novel causal prophylactic antimalarial agents has been the Plasmodium cynomolgi sporozoite-infected Indian-origin rhesus monkey. In 2009 the model was reassessed with 3 clinical standards: primaquine (PQ), Tafenoquine (TQ), and atovaquone-proguanil. Both control monkeys were parasitemic on day 8 post-sporozoite inoculation on day 0. Primaquine at 1.78 mg base/kg/day on days (−1) to 8 protected 1 monkey and delayed parasitemia patency of the other monkey to day 49. Tafenoquine at 6 mg base/kg/day on days (−1) to 1 protected both monkeys. However, atovaquone-proguanil at 10 mg atovaquone/kg/day on days (−1) to 8 did not protect either monkey and delayed patency only to days 18–19. Primaquine and TQ at the employed regimens are proposed as appropriate doses of positive control drugs for the model at present.
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randomized double blind study of the safety tolerability and efficacy of Tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Peter Nasveld, Scott Kitchener, Michael D. Edstein, Mark Reid, Leonard Brennan, Ivor Harris, Peter A Leggat, Philip Pickford, Caron Kerr, Colin OhrtAbstract:This study represents the first phase III trial of the safety, tolerability, and effectiveness of Tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg Tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, Tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (Tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on Tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the Tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of Tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, Tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.
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a new primaquine analogue Tafenoquine wr 238605 for prophylaxis against plasmodium falciparum malaria
Clinical Infectious Diseases, 2001Co-Authors: Dennis G Shanks, Colin Ohrt, Aggrey J Oloo, G M Aleman, Francis W Klotz, David J Braitman, John R Horton, Ralf P BruecknerAbstract:We tested Tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of Tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of Tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of Tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg Tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of Tafenoquine, taken weekly for less than or equal to 13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.
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a new primaquine analogue Tafenoquine wr 238605 for prophylaxis against plasmodium falciparum malaria
Clinical Infectious Diseases, 2001Co-Authors: Dennis G Shanks, Colin Ohrt, Aggrey J Oloo, G M Aleman, Francis W Klotz, David J Braitman, John R Horton, Ralf P BruecknerAbstract:We tested Tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of Tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of Tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of Tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg Tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of Tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.
Peter Nasveld - One of the best experts on this subject based on the ideXlab platform.
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Tafenoquine in the prophylaxis and treatment of malaria in australian defence force personnel
2011Co-Authors: Peter NasveldAbstract:The Australian Defence Force has a long history of exposure to malaria and frequently deploys into the immediate area of the Pacific Rim where drug resistance has been noted to be problematic. In the late 1990s failures of established malaria prophylaxis regimens were beginning to become more prevalent within the ADF and a search was commenced to identify alternative or promising emerging prophylaxis and treatment regimens. In this context the work presented within this thesis was undertaken with a new 8-aminoquinolone antimalarial, initially formulated by the United States Army's Walter Reed Army Institute of Research (WRAIR) and identified as investigative compound WR 238605. The thesis investigates its utility as both prophylaxis and treatment for malaria infection. The compound was subsequently identified in a joint development arrangement between the US Army and GlaxoSmithKline as etaquine, before a final naming of the compound as Tafenoquine. The thesis presents three distinct challenges in the development of this promising antimalarial drug and describes the early human use of Tafenoquine in the following settings: • Prophylaxis against malaria infection during deployment to a malarious area; • Post exposure prophylaxis of malaria on return from a malarious area; and • Treatment of recurrences of malaria infection. Methods: The thesis is developed through the description of three distinct human clinical trials. Each of these will be developed as individual chapters within the thesis although the reality is that there was some overlap between the activities with developments observed in early activity being used to define both later stages of long term trials and inform the development of the newer activities, some of which are now ongoing in other countries and research institutions. The first double blind comparative study investigates the use of Tafenoquine and mefloquine for the longer term (6 months) prophylaxis of malaria in Australian Defence personnel on deployment to Timor Leste. The second, an open label comparative study of the use of Tafenoquine and primaquine in the post exposure prophylaxis of vivax malaria in a defence population in Bougainville, Papua New Guinea and in Timor Leste, and the third looks at the treatment of recurring vivax malaria with Tafenoquine in an open label study in a non randomised population of defence personnel. Results: Prophylaxis against malaria infection during deployment to a malarious area: Tafenoquine at a weekly dose of 200mg and mefloquine at a dose of 250mg were well tolerated amongst subjects in a military deployment. No malaria occurred in either the Tafenoquine and mefloquine arms during the prophylactic phase of this Phase III study. During the relapse follow-up phase, <1% of subjects in either treatment group developed Plasmodium vivax malaria. The incidence and nature of adverse events was similar between the two treatment groups. The most common adverse events were gastroenteritis and unrelated injury. Tafenoquine was associated with the development of vortex keratopathy (secondary to phospholipidosis) in 69/74 (93.2%) subjects tested (compared to no mefloquine subjects). This effect was benign and reversible, with resolution in >90% subjects at 6 months and complete resolution in all subjects by 1 year post-treatment. No significant changes were seen in most laboratory indices during the study. Increases in methaemoglobin in the Tafenoquine group were small. Renal follow-up confirmed a lack of long-term renal effects of Tafenoquine. Post exposure prophylaxis of malaria on return from a malarious area: A 3-day dosing regimen of Tafenoquine (400 mg od, 200 mg bd or 200 mg od) was effective as a post-exposure prophylaxis agent in this study, demonstrating similar efficacy to 14-day primaquine. Tafenoquine, with a shorter dosing regimen (3 days compared to 14 days primaquine), could be used as a more convenient, yet effective, post-exposure prophylaxis agent. Tafenoquine was well tolerated, with no subjects being withdrawn due to adverse events. The most common adverse events were gastrointestinal events. Treatment of recurrences of malaria infection: This small scale study showed that Tafenoquine is safe and effective (following chloroquine treatment) in prevention of relapse of multi-relapsing vivax malaria. The management of relapsing vivax malaria with chloroquine/Tafenoquine may be more effective and convenient in preventing further relapses than the standard chloroquine/primaquine treatment regimen. Larger studies are required to address the effectiveness and tolerability of chloroquine/Tafenoquine for the treatment of vivax malaria. There is also a requirement to more extensively address Tafenoquine used on its own for the treatment of recurring vivax malaria. There remains a need to investigate this regimen in other ethnic populations, including special risk groups such as children and pregnant women. Conclusions: Tafenoquine displays the properties required of a promising antimalarial compound. It has, in two phase III clinical trials, established prophylaxis properties; a demonstrated advantage over the classical 14 days of primaquine treatment for post exposure prophylaxis against P. vivax in its reduced treatment time of 3 days; and has a suggested role in the management of recurrences of vivax malaria, although further research will be required to firmly establish this role. It has an acceptable adverse event profile in the limited treatments undertaken to date, when compared to other available antimalarial compounds. Additionally, it has the advantage of once weekly dosing and shorter post exposure prophylaxis regimens when compared to other available treatments.
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randomized double blind study of the safety tolerability and efficacy of Tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Peter Nasveld, Scott Kitchener, Michael D. Edstein, Mark Reid, Leonard Brennan, Ivor Harris, Peter A Leggat, Philip Pickford, Caron Kerr, Colin OhrtAbstract:This study represents the first phase III trial of the safety, tolerability, and effectiveness of Tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg Tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, Tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (Tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on Tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the Tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of Tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, Tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.
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the efficacy and tolerability of three different regimens of Tafenoquine versus primaquine for post exposure prophylaxis of plasmodium vivax malaria in the southwest pacific
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2008Co-Authors: Nathan Elmes, Peter Nasveld, Scott Kitchener, D A KociskoAbstract:Tafenoquine is being developed for radical cure and post-exposure prophylaxis of Plasmodium vivax malaria. In an open-label study, 1512 Australian Defence Force personnel received one of three Tafenoquine 3 d regimens [400 mg once daily (od), 200 mg twice daily (bid), 200 mg od] or daily primaquine (22.5 mg) plus doxycycline (100 mg) over 14 d in Bougainville and in Timor-Leste for post-exposure prophylaxis. The relapse rate of subjects treated in Bougainville with Tafenoquine (n = 173) was 1.2% (200 mg bid × 3 d) and 2.3% (400 mg od × 3 d), while primaquine plus doxycycline (n = 175) was 3.4%. For subjects treated in Timor-Leste with Tafenoquine (n = 636), the relapse rate was 4.9% (200 mg od × 3 d), 5.3% (200 mg bid × 3 d) and 11.0% (400 mg od × 3d), while primaquine plus doxycycline (n = 289) was 10.0%. The most frequent adverse events reported across all groups were nausea, abdominal distress and diarrhoea. There was a dose-dependent reduction in adverse events with a reduced dose of Tafenoquine, with the lowest dose (total 600 mg over 3 d) producing rates of adverse events equivalent to that of primaquine plus doxycycline. The much shorter dosing regimen of Tafenoquine should increase compliance, which is often suboptimal with primaquine after leaving an endemic area. [Australian New Zealand Clinical Trials Registry Number 12607000588493].
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population pharmacokinetics of Tafenoquine during malaria prophylaxis in healthy subjects
Antimicrobial Agents and Chemotherapy, 2007Co-Authors: B G Charles, Peter Nasveld, Mark Reid, Ivor Harris, Ann K Miller, Michael D. EdsteinAbstract:The population pharmacokinetics of Tafenoquine were studied in Australian soldiers taking Tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg Tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg Tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma Tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for Tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma Tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of Tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.
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Tafenoquine for the treatment of recurrent Plasmodium vivax malaria
American Journal of Tropical Medicine and Hygiene, 2007Co-Authors: Scott Kitchener, Peter Nasveld, Michael D. EdsteinAbstract:Tafenoquine was used to treat Plasmodium vivax malaria cases who had previously failed treatment with chloroquine and primaquine. Chloroquine was followed by a loading dose of Tafenoquine (200 mg base/day for 3 days) and 200 mg a week was given for 8 weeks. One of 27 treated patients relapsed after 6 months of observation. A standard course of chloroquine administered with 8 weeks of Tafenoquine may be more effective than chloroquine with primaquine (22.5 mg/day for 14 days) in preventing additional P. vivax relapses. Larger studies are required to optimize the combination, but our findings suggest that an extended use of Tafenoquine may be required to prevent relapses of primaquine-tolerant strains of P. vivax malaria.
Stephen Toovey - One of the best experts on this subject based on the ideXlab platform.
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neurological and psychiatric safety of Tafenoquine in plasmodium vivax relapse prevention a review
Malaria Journal, 2020Co-Authors: Stephan Duparc, Stephan Chalon, Scott Miller, Naomi Richardson, Stephen TooveyAbstract:Tafenoquine is an 8-aminoquinoline anti-malarial drug recently approved as a single-dose (300 mg) therapy for Plasmodium vivax relapse prevention, when co-administered with 3-days of chloroquine or other blood schizonticide. Tafenoquine 200 mg weekly after a loading dose is also approved as travellers’ prophylaxis. The development of Tafenoquine has been conducted over many years, using various dosing regimens in diverse populations. This review brings together all the preclinical and clinical data concerning Tafenoquine central nervous system safety. Data were assembled from published sources. The risk of neuropsychiatric adverse events (NPAEs) with single-dose Tafenoquine (300 mg) in combination with chloroquine to achieve P. vivax relapse prevention is particularly examined. There was no evidence of neurotoxicity with Tafenoquine in preclinical animal models. In clinical studies in P. vivax relapse prevention, nervous system adverse events, mainly headache and dizziness, occurred in 11.4% (36/317) of patients with Tafenoquine (300 mg)/chloroquine versus 10.2% (19/187) with placebo/chloroquine; and in 15.5% (75/483) of patients with Tafenoquine/chloroquine versus 13.3% (35/264) with primaquine (15 mg/day for 14 days)/chloroquine. Psychiatric adverse events, mainly insomnia, occurred in 3.8% (12/317) of patients with Tafenoquine/chloroquine versus 2.7% (5/187) with placebo/chloroquine; and in 2.9% (14/483) of patients with Tafenoquine/chloroquine versus 3.4% (9/264) for primaquine/chloroquine. There were no serious or severe NPAEs observed with Tafenoquine (300 mg)/chloroquine in these studies. The risk:benefit of single-dose Tafenoquine/chloroquine in P. vivax relapse prevention is favourable in the presence of malaria, with a low risk of NPAEs, similar to that seen with chloroquine alone or primaquine/chloroquine.
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Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8 aminoquinolines
Malaria Journal, 2018Co-Authors: Judith Berman, Geoffrey S. Dow, Tracey Brown, Stephen TooveyAbstract:Tafenoquine was recently approved for Plasmodium vivax radical cure (KRINTAFEL™) and malaria prevention (ARAKODA™). A review of the non-clinical and clinical literature was conducted to assess whether Tafenoquine (and primaquine) exhibit the same neurologic lesions and associated clinical signs as earlier 8-aminoquinolines, as has been alleged in recent opinion pieces. Plasmocid, pamaquine and pentaquine damage specific neuro-anatomical structures in Rhesus monkeys and humans leading to corresponding deficits in neurologic function. Neurologic therapeutic indices for these 3 drugs calculated based on monkey data were well correlated with human data. Despite 60 years of use, there is no evidence that primaquine exhibits similar neurotoxicity in humans. Extrapolation of data from Rhesus monkeys to humans, and the available clinical data, suggest that Tafenoquine also does not exhibit pamaquine, pentaquine or plasmocid-like clinical neurologic signs in humans.
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Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8-aminoquinolines
Malaria Journal, 2018Co-Authors: Jonathan Berman, Tracey Brown, Geoffrey Dow, Stephen TooveyAbstract:Background Tafenoquine was recently approved for Plasmodium vivax radical cure (KRINTAFEL™) and malaria prevention (ARAKODA™). Methods A review of the non-clinical and clinical literature was conducted to assess whether Tafenoquine (and primaquine) exhibit the same neurologic lesions and associated clinical signs as earlier 8-aminoquinolines, as has been alleged in recent opinion pieces. Results Plasmocid, pamaquine and pentaquine damage specific neuro-anatomical structures in Rhesus monkeys and humans leading to corresponding deficits in neurologic function. Neurologic therapeutic indices for these 3 drugs calculated based on monkey data were well correlated with human data. Despite 60 years of use, there is no evidence that primaquine exhibits similar neurotoxicity in humans. Discussion/conclusions Extrapolation of data from Rhesus monkeys to humans, and the available clinical data, suggest that Tafenoquine also does not exhibit pamaquine, pentaquine or plasmocid-like clinical neurologic signs in humans.
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Tafenoquine for malaria prophylaxis in adults an integrated safety analysis
Travel Medicine and Infectious Disease, 2017Co-Authors: Anne Novittmoreno, Geoffrey S. Dow, Janet Ransom, Bryan Smith, Lisa T Read, Stephen TooveyAbstract:Background Tafenoquine is a new prophylactic antimalarial drug. The current analysis presents an integrated safety assessment of the Tafenoquine Anticipated Clinical Regimen (Tafenoquine ACR) from 5 clinical trials, including 1 conducted in deployed military personnel and 4 in non-deployed residents, which also incorporated placebo and mefloquine comparator groups.
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Tafenoquine is not neurotoxic following supertherapeutic dosing in rats
Travel Medicine and Infectious Disease, 2017Co-Authors: Geoffrey S. Dow, Mark Reid, Bryan Smith, Tracey Brown, Stephen TooveyAbstract:Abstract Background Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. Methods The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of Tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. Results At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7–8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). Conclusions As in humans, adverse events other than neurotoxicity were dose-limiting for Tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future.
Dennis G Shanks - One of the best experts on this subject based on the ideXlab platform.
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a retrospective analysis of the protective efficacy of Tafenoquine and mefloquine as prophylactic anti malarials in non immune individuals during deployment to a malaria endemic area
Malaria Journal, 2014Co-Authors: Geoffrey S. Dow, Douglas B. Tang, Mark Reid, Bryan Smith, William F Mccarthy, Dennis G ShanksAbstract:In 2000/2001, the Australian Defense Forces (ADF), in collaboration with SmithKline Beecham and the United States Army, conducted a field trial to evaluate the safety, tolerability and efficacy of Tafenoquine and mefloquine/primaquine for the prophylaxis of malaria amongst non-immune Australian soldiers deployed to East Timor (now called Timor Leste) for peacekeeping operations. The lack of a concurrent placebo control arm prevented an internal estimate of the malaria attack rate and so the protective efficacy of the study regimens was not determined at the time. In a retrospective analysis of the trial results, the all species malaria attack rate was estimated for the prophylactic phase of the study which was defined as the period between administration of the first prophylactic dose and the first dose of post-deployment medication. First, the Plasmodium vivax attack rate was estimated during the prophylactic phase of the deployment by adjusting the observed P. vivax relapse rate during post-deployment to account for the known anti-relapse efficacies (or effectiveness) of the study medications (determined from prior studies). The all species malaria attack rate (P. vivax and Plasmodium falciparum) was then determined by adjusting the P. vivax attack rate based on the ratio of P. falciparum to P. vivax observed during prior ADF deployments to Timor Leste. This estimated all species malaria attack rate was then used as the ‘constant estimated attack rate’ in the calculation of the protective efficacy of Tafenoquine and mefloquine during the prophylactic phase of the deployment. The estimated attack rate during the prophylactic phase of the study was determined to be 7.88%. The protective efficacies of Tafenoquine and mefloquine, with corresponding 95% confidence intervals (95% CI), were determined to be 100% (93%-100%) and 100% (79%-100%) respectively. The protective efficacy of Tafenoquine (200 mg per day for three days, followed by weekly 200 mg maintenance doses) is similar to that of the weekly standard of care (mefloquine, 250 mg).
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a new primaquine analogue Tafenoquine wr 238605 for prophylaxis against plasmodium falciparum malaria
Clinical Infectious Diseases, 2001Co-Authors: Dennis G Shanks, Colin Ohrt, Aggrey J Oloo, G M Aleman, Francis W Klotz, David J Braitman, John R Horton, Ralf P BruecknerAbstract:We tested Tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of Tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of Tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of Tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg Tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of Tafenoquine, taken weekly for less than or equal to 13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.
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a new primaquine analogue Tafenoquine wr 238605 for prophylaxis against plasmodium falciparum malaria
Clinical Infectious Diseases, 2001Co-Authors: Dennis G Shanks, Colin Ohrt, Aggrey J Oloo, G M Aleman, Francis W Klotz, David J Braitman, John R Horton, Ralf P BruecknerAbstract:We tested Tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of Tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of Tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of Tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg Tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of Tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.
