An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia

Leang, Rithea; Khu, Naw Htee; Mukaka, Mavuto; Debackere, Mark; Tripura, Rupam; Kheang, Soy Ty; Chy, Sophy; Kak, Neeraj; Buchy, Philippe; Tarantola, Arnaud; Ménard, Didier; Roca-Felterer, Arantxa; Fairhurst, Rick M.; Kheng, Sim; Muth, Sinoun; Song, Ngak; Dondorp, Arjen M.; White, Nicholas J.; Taylor, Walter

doi:10.1186/s12916-016-0701-8

Cited by 16 publications

(21 citation statements)

References 85 publications

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“…Higher doses are more effective but their use is limited by concerns over safety in subjects with reduced G6PD activity. Results from a recent study resulted in a proposal to dose primaquine by age group [144]. The clinical activity of low-dose primaquine sets the bar for the next generation of compounds.…”

Section: Tcp-5: Transmission Blockingmentioning

confidence: 99%

New developments in anti-malarial target candidate and product profiles

Burrows

Duparc

Gutteridge

et al. 2017

Malar J

410

480

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A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

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Section: Tcp-5: Transmission Blockingmentioning

confidence: 99%

New developments in anti-malarial target candidate and product profiles

Burrows

Duparc

Gutteridge

et al. 2017

Malar J

410

480

View full text Add to dashboard Cite

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“…Regardless of its safety profile and pharmacokinetic features, IVM is prescribed for all its indications in weight (or height) based regimens, which difficult its administration in MDA interventions and introduces the risk of under-dosing [ 21 ]. A fixed and high dose regimen which takes advantage of the wide therapeutic index of IVM is an attractive alternative for improving the distribution and therefore potentially increasing coverage rates of treatment campaigns as has been the case for primaquine in the treatment of malaria [ 22 ]. Moreover, a safe and efficacious fixed-dose IVM in formulations different than the traditional 3 and 6 mg tablets would be required if co-formulated with other anthelmintics such as albendazole.…”

Section: Introductionmentioning

confidence: 99%

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

et al. 2018

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Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective.Trial registrationClinicalTrials.gov NCT03173742.

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“…The effective ACT regimen should be used for both Pf and Pv blood stages. Primaquine in standard dosages should be used for Pf gametocytes and Pv hypnozoites in countries where these doses are already being used as standard of care (e.g., Vietnam) or low-dose [82] for Pf gametocytes in areas where there are safety concerns. We believe that all patients in the GMS should have visits on days 28 and 42 to detect late-treatment failure, as well as to have malaria patients and their work groups be transmission-stopping ambassadors.…”

Section: Towards Malaria Elimination -A Leap Forwardmentioning

confidence: 99%

Preparing for the Next Global Threat: A Call for Targeted, Immediate Decisive Action in Southeast Asia to Prevent the Next Pandemic in Africa

Ohrt¹,

Ngo²,

Nguyen³

2018

Towards Malaria Elimination - A Leap Forward

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Global investments have had great impact on malaria-these are now at risk of being reversed. Cambodia is where drug resistance historically emerges and spreads globally to drive resulting pandemics-we are currently watching history repeat itself. Despite large investments and recent success in driving down overall rates of malaria, high levels of resistance to nearly all antimalarial drugs are now widespread in Cambodia. Malaria cases are again rising in both Cambodia and Vietnam. Nearly incurable malaria in this region is a real and present threat. Critical actions to prevent further spread of the emerging incurable parasites are: (1) Commitment and real sense of urgency through declaration of a "Public Health Emergency of International Concern" or a similar set of directives; (2) Establish leadership with sufficient authority, respect, expertise and operational funding; (3) Engage affected security forces to stop disease transmission and support elimination operations; (4) Utilize surveillance as a core intervention with result-based funding targeting malaria transmission foci with rapid and effective action. Immediate decisive action is needed in Southeast Asia to prevent the next malaria pandemic. This chapter highlights persistent gaps in the region with methods to address them. In 2015-2016, our collaboration with NIMPE pilot tested tools to intervene in actual forest transmission foci. Our study district saw a 96% decrease in malaria from 2014 to 2017, with the entire province seeing the largest decrease in Central Vietnam in this same timeframe. We describe methods to tackle transmission foci, with both an integrated prevention and treatment package. We call on all stakeholders to make changes to current investments to address this critical challenge.

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An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia

Cited by 16 publications

References 85 publications

New developments in anti-malarial target candidate and product profiles

New developments in anti-malarial target candidate and product profiles

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

Preparing for the Next Global Threat: A Call for Targeted, Immediate Decisive Action in Southeast Asia to Prevent the Next Pandemic in Africa

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