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

ABSTRACT: In 2012, the World Health Organization recommended the addition of single low-dose primaquine (SLDPQ, 0.25 mg base/kg body weight) to artemisinin combination therapies to block the transmission of Plasmodium falciparum without testing for glucose-6-phosphate dehydrogenase deficiency. The targeted group was non-pregnant patients aged???1 year (later changed to???6 months) with acute uncomplicated falciparum malaria, primarily in countries with artemisinin-resistant P. falciparum (ARPf). No dosing regimen was suggested, leaving malaria control programmes and clinicians in limbo. Therefore, we designed a user-friendly, age-based SLDPQ regimen for Cambodia, the country most affected by ARPf.By reviewing primaquine's pharmacology, we defined a therapeutic dose range of 0.15-0.38 mg base/kg (9-22.5 mg in a 60-kg adult) for a therapeutic index of 2.5. Primaquine doses (1-20 mg) were tested using a modelled, anthropometric database of 28,138 Cambodian individuals (22,772 healthy, 4119 with malaria and 1247 with other infections); age distributions were: 0.5-4 years (20.0 %, n?=?5640), 5-12 years (9.1 %, n?=?2559), 13-17 years (9.1 %, n?=?2550), and???18 years (61.8 %, n?=?17,389). Optimal age-dosing groups were selected according to calculated mg base/kg doses and proportions of individuals receiving a therapeutic dose.Four age-dosing bands were defined: (1) 0.5-4 years, (2) 5-9 years, (3) 10-14 years, and (4) ?15 years to receive 2.5, 5, 7.5, and 15 mg of primaquine base, resulting in therapeutic doses in 97.4 % (5494/5640), 90.5 % (1511/1669), 97.7 % (1473/1508), and 95.7 % (18,489/19,321) of individuals, respectively. Corresponding median (1st-99th centiles) mg base/kg doses of primaquine were (1) 0.23 (0.15-0.38), (2) 0.29 (0.18-0.45), (3) 0.27 (0.15-0.39), and (4) 0.29 (0.20-0.42).This age-based SLDPQ regimen could contribute substantially to malaria elimination and requires urgent evaluation in Cambodia and other countries with similar anthropometric characteristics. It guides primaquine manufacturers on suitable tablet strengths and doses for paediatric-friendly formulations. Development of similar age-based dosing recommendations for Africa is needed.

SUBMITTER: Leang R

PROVIDER: S-EPMC5081959 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Leang Rithea R Khu Naw Htee NH Mukaka Mavuto M Debackere Mark M Tripura Rupam R Kheang Soy Ty ST Chy Say S Kak Neeraj N Buchy Philippe P Tarantola Arnaud A Menard Didier D Roca-Felterer Arantxa A Fairhurst Rick M RM Kheng Sim S Muth Sinoun S Ngak Song S Dondorp Arjen M AM White Nicholas J NJ Taylor Walter Robert John WR

BMC medicine 20161027 1

<h4>Background</h4>In 2012, the World Health Organization recommended the addition of single low-dose primaquine (SLDPQ, 0.25 mg base/kg body weight) to artemisinin combination therapies to block the transmission of Plasmodium falciparum without testing for glucose-6-phosphate dehydrogenase deficiency. The targeted group was non-pregnant patients aged ≥ 1 year (later changed to ≥ 6 months) with acute uncomplicated falciparum malaria, primarily in countries with artemisinin-resistant P. falciparu ...[more]

PMID: 27784313

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Project description:BACKGROUND:In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. METHODS:Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ?6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ?6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. RESULTS:From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n?=?39,886, 6.03%), (ii) 1-5 years (n?=?261,036, 45.46%), (iii) 6-9 years (n?=?20,770, 3.14%), (iv) 10-14 years (n?=?12,155, 1.84%) and (v) ?15 years (n?=?328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. CONCLUSIONS:We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5?-?11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Project description:BackgroundLow-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA). Uncertainty about the therapeutic dose range (TDR) required for general and paediatric populations challenge the implementation of the World Health Organisation's recommendation to add 0.25 mg/kg to current standard antimalarial treatment in such settings. Modelling work shows that for low-dose primaquine to have an impact, high efficacy and extensive population coverage are needed. In practice, age-based dose regimens, often used in MDA, could lead to safety concerns and a different effectiveness profile. We aimed to define TDRs for primaquine and to assess dosing accuracy of age-based dose regimens.MethodsOptimised regional age-based dosing regimens for low-dose primaquine were developed in steps. First, we identified potential TDR options based on suggested published efficacy and safety thresholds (i.e. 0.1-0.4, 0.125-0.375, 0.15-0.35 mg/kg). We then used our previously defined weight-for-age growth references and age-based dose optimisation tool to model predicted regimen accuracies for Africa, Asia and Latin America based on low-dose primaquine tablets (3.75 mg and 7.5 mg) currently under development by Sanofi while employing the identified dose range options and pre-specified regimen characteristics.ResultsDose regimens employing TDRs of 0.1-0.4 and 0.125-0.375 mg/kg had the highest average predicted dose accuracies in all regions with the widest dose range of 0.1-0.4 mg/kg resulting in ≥99% dose accuracy in all three regions. The narrower 0.15-0.35 mg/kg range was on average predicted to correctly dose 91.4% of the population in Africa, 93.2% in Asia and 92.6% in Latin America. This range would prescribe ≥20% of 3-year-olds doses below 0.15 mg/kg and ≥20% of 11-year-olds doses above 0.35 mg/kg. Widening the TDR from 0.15-0.35 to 0.1-0.4 mg/kg increased the dose accuracy by ≥20% in Africa, ≥15% in Asia and ≥10% in Latin America.ConclusionOptimised age-based dose regimens derived from wider TDRs are predicted to attain the dose accuracies required for effective MDA in malaria transmission reduction and elimination settings. We highlight the need for a clearly defined TDR and for safety and efficacy trials to focus on doses compatible with age-based dosing often employed in such settings.

Project description:BackgroundIn many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax.MethodsThe recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen.ResultsThe proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day.ConclusionThe proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Project description:BackgroundSingle low dose primaquine (SLD PQ, 0.25mg/kg) is recommended in combination with artemisinin-based combination therapy (ACT) as a gametocytocide to prevent Plasmodium falciparum transmission in areas threatened by artemisinin resistance. To date, no randomized controlled trials have measured primaquine's effect on infectiousness to Anopheline mosquitoes in Southeast Asia.MethodsCambodian adults with uncomplicated falciparum malaria were randomized to receive a single 45mg dose of primaquine (equivalent to three SLD PQ) or no primaquine after the third dose of dihydroartemisin-piperaquine (DHP) therapy. A membrane-feeding assay measured infectiousness to Anopheles dirus on days 0, 3, 7, and 14 of blood-stage therapy. Gametocytemia was evaluated by microscopy and reverse-transcriptase PCR.ResultsPrior to trial halt for poor DHP treatment efficacy, 101 participants were randomized and 50 received primaquine. Overall microscopic gametocyte prevalence was low (9%), but gametocytemic subjects given primaquine were gametocyte-free by day 14, and significantly less likely to harbor gametocytes by day 7 compared to those treated with DHP-alone, who remained gametocytemic for a median of two weeks. Only one infectious subject was randomized to the primaquine group, precluding assessment of transmission-blocking efficacy. However, he showed a two-fold reduction in oocyst density of infected mosquitoes less than 24 hours after primaquine dosing. In the DHP-alone group, four subjects remained infectious through day 14, infecting roughly the same number of mosquitoes pre and post-treatment. Overall, microscopic gametocytemia was an excellent predictor of infectiousness, and performed better than submicroscopic gametocytemia post-treatment, with none of 474 mosquitoes infected post-treatment arising from submicroscopic gametocytes.ConclusionsIn a setting of established ACT resistance, a single dose of 45mg primaquine added to DHP rapidly and significantly reduced gametocytemia, while DHP-alone failed to reduce gametocytemia and prevent malaria transmission to mosquitoes. Continued efforts to make single dose primaquine widely available are needed to help achieve malaria elimination.

Project description:BackgroundDespite progress in malaria control, malaria remains an important public health concern in Cambodia, mostly linked to forested areas. Large-scale vector control interventions in Cambodia are based on the free distribution of long-lasting insecticidal nets (LLINs), targeting indoor- and late-biting malaria vectors only. The present study evaluated the vector density, early biting activity and malaria transmission of outdoor-biting malaria vectors in two forested regions in Cambodia.MethodsIn 2005 two entomological surveys were conducted in 12 villages and their related forest plots in the east and west of Cambodia. Mosquitoes were collected outdoors by human landing collections and subjected to enzyme-linked immunosorbent assay (ELISA) to detect Plasmodium sporozoites after morphological identification. Blood samples were collected in the same villages for serological analyses. Collected data were analysed by the classification and regression tree (CART) method and linear regression analysis.ResultsA total of 11,826 anophelines were recorded landing in 787 man-night collections. The majority (82.9%) were the known primary and secondary vectors. Most of the variability in vector densities and early biting rates was explained by geographical factors, mainly at village level. Vector densities were similar between forest and village sites. Based on ELISA results, 29% out of 17 Plasmodium-positive bites occurred before sleeping time, and 65% in the forest plots. The entomological inoculation rates of survey 1 were important predictors of the respective seroconversion rates in survey 2, whereas the mosquito densities were not.DiscussionIn Cambodia, outdoor malaria transmission in villages and forest plots is important. In this context, deforestation might result in lower densities of the primary vectors, but also in higher densities of secondary vectors invading deforested areas. Moreover, higher accessibility of the forest could result in a higher man-vector contact. Therefore, additional vector control measures should be developed to target outdoor- and early-biting vectors.

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

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

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