Optimal balance of benefit versus risk for tafenoquine in the treatment of Plasmodium vivax malaria.

A single 300 mg dose of tafenoquine (an 8-aminoquinoline), in combination with a standard 3-day course of chloroquine, is approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥ 16 years. Despite this, questions have arisen on the optimal dose of tafenoquine. Before the availability of tafenoquine, a 3-day course of chloroquine in combination with the 8-aminoquinoline primaquine was the only effective radical cure for vivax malaria. The World Health Organization (WHO)-recommended standard regimen is 14 days of primaquine 0.25 mg/kg/day or 7 days of primaquine 0.5 mg/kg/day in most regions, or 14 days of primaquine 0.5 mg/kg/day in East Asia and Oceania, however the long treatment courses of 7 or 14 days may result in poor adherence and, therefore, low treatment efficacy. A single dose of tafenoquine 300 mg in combination with a 3-day course of chloroquine is an important advancement for the radical cure of vivax malaria in patients without glucose-6-phosphate dehydrogenase (G6PD) deficiency, as the use of a single-dose treatment will improve adherence. Selection of a single 300 mg dose of tafenoquine for the radical cure of P. vivax malaria was based on collective efficacy and safety data from 33 studies involving more than 4000 trial participants who received tafenoquine, including over 800 subjects who received the 300 mg single dose. The safety profile of single-dose tafenoquine 300 mg is similar to that of standard-dosage primaquine 0.25 mg/kg/day for 14 days. Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency; severe haemolysis can lead to anaemia, kidney damage, and, in some cases, death. Therefore, relapse prevention using an 8-aminoquinoline must be balanced with the need to avoid clinical haemolysis associated with G6PD deficiency. To minimize this risk, the WHO recommends G6PD testing for all individuals before the administration of curative doses of 8-aminoquinolines. In this article, the authors review key efficacy and safety data from the pivotal trials of tafenoquine and argue that the currently approved dose represents a favourable benefit-risk profile.

Population pharmacokinetics of primaquine and its metabolites in African males.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites' pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants.

Current guidelines advise against primaquine treatment for breastfeeding mothers to avoid the potential for haemolysis in infants with G6PD deficiency. To predict the haemolytic risk, the amount of drug received from the breast milk and the resulting infant drug exposure need to be characterised. Here, we develop a pharmacokinetic model to describe the drug concentrations in breastfeeding women using venous, capillary, and breast milk data. A mother-to-infant model is developed to mimic the infant feeding pattern and used to predict their drug exposures. Primaquine and carboxyprimaquine exposures in infants are <1% of the exposure in mothers. Therefore, even in infants with the most severe G6PD deficiency variants, it is highly unlikely that standard doses of primaquine (0.25-1 mg base/kg once daily given to the mother for 1-14 days) would cause significant haemolysis. After the neonatal period, primaquine should not be restricted for breastfeeding women (Clinical Trials Registration: NCT01780753).

Operational effectiveness of tafenoquine and primaquine for the prevention of Plasmodium vivax recurrence in Brazil: a retrospective observational study.

BACKGROUND: Prevention of Plasmodium vivax malaria recurrence is essential for malaria elimination in Brazil. We evaluated the real-world effectiveness of an updated treatment algorithm for P vivax radical cure in the Brazilian Amazon. METHODS: In this non-interventional observational study, we used retrospective data from the implementation of a P vivax treatment algorithm at 43 health facilities in Manaus and Porto Velho, Brazil. The treatment algorithm consisted of chloroquine (25 mg/kg over 3 days) and point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing followed by single-dose tafenoquine 300 mg (G6PD normal, aged ≥16 years, not pregnant and not breastfeeding), 7-day primaquine 0·5 mg/kg per day (G6PD intermediate or normal, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month), or primaquine 0·75 mg/kg per week for 8 weeks (G6PD deficient, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month). P vivax recurrences were identified from probabilistic linkage of routine patient records from the Brazilian malaria epidemiological surveillance system. Recurrence-free effectiveness at day 90 and day 180 was estimated using Kaplan-Meier analysis and hazard ratios (HRs) by multivariate analysis. This clinical trial is registered with ClinicalTrials.gov, NCT05096702, and is completed. FINDINGS: Records from Sept 9, 2021, to Aug 31, 2022, included 5554 patients with P vivax malaria. In all treated patients of any age and any G6PD status, recurrence-free effectiveness at day 180 was 75·8% (95% CI 74·0-77·6) with tafenoquine, 73·4% (71·9-75·0) with 7-day primaquine, and 82·1% (77·7-86·8) with weekly primaquine. In patients aged at least 16 years who were G6PD normal, recurrence-free effectiveness until day 90 was 88·6% (95% CI 87·2-89·9) in those who were treated with tafenoquine (n=2134) and 83·5% (79·8-87·4) in those treated with 7-day primaquine (n=370); after adjustment for confounding factors, the HR for recurrence following tafenoquine versus 7-day primaquine was 0·65 (95% CI 0·49-0·86; p=0·0031), with similar outcomes between the two treatments at day 180 (log-rank p=0·82). Over 180 days, median time to recurrence in patients aged at least 16 years who were G6PD normal was 92 days (IQR 76-120) in those treated with tafenoquine and 68 days (52-94) in those treated with 7-day primaquine. INTERPRETATION: In this real-world setting, single-dose tafenoquine was more effective at preventing P vivax recurrence in patients aged at least 16 years who were G6PD normal compared with 7-day primaquine at day 90, while overall efficacy at 180 days was similar. The public health benefits of the P vivax radical cure treatment algorithm incorporating G6PD quantitative testing and tafenoquine support its implementation in Brazil and potentially across South America. FUNDING: Brazilian Ministry of Health, Municipal and State Health Secretariats; Fiocruz; Medicines for Malaria Venture; Bill & Melinda Gates Foundation; Newcrest Mining; and the UK Government. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: In most of the Americas, the recommended treatment to prevent relapse of Plasmodium vivax malaria is primaquine at a total dose of 3.5 mg per kilogram of body weight, despite evidence of only moderate efficacy. METHODS: In this trial conducted in Brazil, we evaluated three primaquine regimens to prevent relapse of P. vivax malaria in children at least 5 years of age and in adults with microscopy-confirmed P. vivax monoinfection. All the patients received directly observed chloroquine for 3 days (total dose, 25 mg per kilogram). Group 1 received a total primaquine dose of 3.5 mg per kilogram (0.5 mg per kilogram per day) over 7 days with unobserved administration; group 2 received the same regimen as group 1 but with observed administration; and group 3 received a total primaquine dose of 7.0 mg per kilogram over 14 days (also 0.5 mg per kilogram per day) with observed administration. We monitored the patients for 168 days. RESULTS: We enrolled 63 patients in group 1, 96 in group 2, and 95 in group 3. The median age of the patients was 22.4 years (range, 5.4 to 79.8). By day 28, three P. vivax recurrences were observed: 2 in group 1 and 1 in group 2. By day 168, a total of 70 recurrences had occurred: 24 in group 1, 34 in group 2, and 12 in group 3. No serious adverse events were noted. On day 168, the percentage of patients without recurrence was 58% (95% confidence interval [CI], 44 to 70) in group 1, 59% (95% CI, 47 to 69) in group 2, and 86% (95% CI, 76 to 92) in group 3. Survival analysis showed a difference in the day 168 recurrence-free percentage of 27 percentage points (97.5% CI, 10 to 44; P<0.001) between group 1 and group 3 and a difference of 27 percentage points (97.5% CI, 12 to 42; P<0.001) between group 2 and group 3. CONCLUSIONS: The administration of primaquine at a total dose of 7.0 mg per kilogram had higher efficacy in preventing relapse of P. vivax malaria than a total dose of 3.5 mg per kilogram through day 168. (Supported by the U.S. Agency for International Development; ClinicalTrials.gov number, NCT03610399.).

Safety monitoring experience of single-low dose primaquine co-administered with artemether-lumefantrine among providers and patients in routine healthcare practice: a qualitative study in Eastern Tanzania.

BACKGROUND: Primaquine is a gametocytocidal drug recommended by the World Health Organization (WHO) in a single-low dose combined with artemisinin-based combination therapy (ACT) for the treatment and prevention of Plasmodium falciparum malaria transmission. Safety monitoring concerns and the lack of a universal validated and approved primaquine pharmacovigilance tool is a challenge for a national rollout in many countries. This study aimed to explore the acceptance, reliability and perceived effectiveness of the primaquine roll out monitoring pharmacovigilance tool (PROMPT). METHODS: This study was conducted in three dispensaries in the Coastal region of Eastern Tanzania. The study held six in-depth interviews with healthcare providers and six participatory focus group discussions with malaria patients (3) and parents/guardians of sick children (3). Participants were purposively sampled. Thematic analysis was conducted with the aid of NVivo qualitative analysis software. RESULTS: The respondents' general acceptance and perceived effectiveness of the single-low dose primaquine and PROMPT was good. Screening procedure for treatment eligibility and explaining to patients about the possible adverse events was considered very useful for safety reasons. Crushing and dissolving of primaquine tablet to get the appropriate dose, particularly in children, was reported by all providers to be challenging. Transport costs and poor access to the health facility were the main reasons for a patient failing to return to the clinic for a scheduled follow-up visit. Treatment was perceived to be safe by both providers and patients and reported no case of a severe adverse event. Some providers were concerned with the haemoglobin drop observed on day 7. CONCLUSION: Single-low dose primaquine was perceived to be safe and acceptable among providers and patients. PROMPT demonstrated to be a reliable and user-friendly tool among providers. Further validation of the tool by involving the National Malaria Control Programme is pivotal to addressing key challenges and facilitating primaquine adoption in the national policy.

Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa.

BACKGROUND: Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. METHODS: A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. RESULTS: The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2-8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11-13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7-8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women ≥ 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. CONCLUSIONS: This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient.

Dynamics of G6PD activity in patients receiving weekly primaquine for therapy of Plasmodium vivax malaria.

BACKGROUND: Acute Plasmodium vivax malaria is associated with haemolysis, bone marrow suppression, reticulocytopenia, and post-treatment reticulocytosis leading to haemoglobin recovery. Little is known how malaria affects glucose-6-phosphate dehydrogenase (G6PD) activity and whether changes in activity when patients present may lead qualitative tests, like the fluorescent spot test (FST), to misdiagnose G6PD deficient (G6PDd) patients as G6PD normal (G6PDn). Giving primaquine or tafenoquine to such patients could result in severe haemolysis. METHODS: We investigated the G6PD genotype, G6PD enzyme activity over time and the baseline FST phenotype in Cambodians with acute P. vivax malaria treated with 3-day dihydroartemisinin piperaquine and weekly primaquine, 0·75 mg/kg x8 doses. RESULTS: Of 75 recruited patients (males 63), aged 5-63 years (median 24), 15 were G6PDd males (14 Viangchan, 1 Canton), 3 were G6PD Viangchan heterozygous females, and 57 were G6PDn; 6 patients had α/ß-thalassaemia and 26 had HbE. Median (range) Day0 G6PD activities were 0·85 U/g Hb (0·10-1·36) and 11·4 U/g Hb (6·67-16·78) in G6PDd and G6PDn patients, respectively, rising significantly to 1·45 (0·36-5·54, p<0.01) and 12·0 (8·1-17·4, p = 0.04) U/g Hb on Day7, then falling to ~Day0 values by Day56. Day0 G6PD activity did not correlate (p = 0.28) with the Day0 reticulocyte counts but both correlated over time. The FST diagnosed correctly 17/18 G6PDd patients, misclassifying one heterozygous female as G6PDn. CONCLUSIONS: In Cambodia, acute P. vivax malaria did not elevate G6PD activities in our small sample of G6PDd patients to levels that would result in a false normal qualitative test. Low G6PDd enzyme activity at disease presentation increases upon parasite clearance, parallel to reticulocytosis. More work is needed in G6PDd heterozygous females to ascertain the effect of P. vivax on their G6PD activities. TRIAL REGISTRATION: The trial was registered (ACTRN12613000003774) with the Australia New Zealand Clinical trials (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363399&isReview=true).

Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.

BACKGROUND: In 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: The 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.

Mass drug administration for the acceleration of malaria elimination in a region of Myanmar with artemisinin-resistant falciparum malaria: a cluster-randomised trial.

BACKGROUND: To contain multidrug-resistant Plasmodium falciparum, malaria elimination in the Greater Mekong subregion needs to be accelerated while current antimalarials remain effective. We evaluated the safety, effectiveness, and potential resistance selection of dihydroartemisinin-piperaquine mass drug administration (MDA) in a region with artemisinin resistance in Myanmar. METHODS: We did a cluster-randomised controlled trial in rural community clusters in Kayin (Karen) state in southeast Myanmar. Malaria prevalence was assessed using ultrasensitive quantitative PCR (uPCR) in villages that were operationally suitable for MDA (villages with community willingness, no other malaria control campaigns, and a population of 50-1200). Villages were eligible to participate if the prevalence of malaria (all species) in adults was greater than 30% or P falciparum prevalence was greater than 10% (or both). Contiguous villages were combined into clusters. Eligible clusters were paired based on P falciparum prevalence (estimates within 10%) and proximity. Community health workers provided routine malaria case management and distributed long-lasting insecticidal bed-nets (LLINs) in all clusters. Randomisation of clusters (1:1) to the MDA intervention group or control group was by public coin-flip. Group allocations were not concealed. Three MDA rounds (3 days of supervised dihydroartemisinin-piperaquine [target total dose 7 mg/kg dihydroartemisinin and 55 mg/kg piperaquine] and single low-dose primaquine [target dose 0·25 mg base per kg]) were delivered to intervention clusters. Parasitaemia prevalence was assessed at 3, 5, 10, 15, 21, 27, and 33 months. The primary outcomes were P falciparum prevalence at months 3 and 10. All clusters were included in the primary analysis. Adverse events were monitored from the first MDA dose until 1 month after the final dose, or until resolution of any adverse event occurring during follow-up. This trial is registered with ClinicalTrials.gov, NCT01872702. FINDINGS: Baseline uPCR malaria surveys were done in January, 2015, in 43 villages that were operationally suitable for MDA (2671 individuals). 18 villages met the eligibility criteria. Three villages in close proximity were combined into one cluster because a border between them could not be defined. This gave a total of 16 clusters in eight pairs. In the intervention clusters, MDA was delivered from March 4 to March 17, from March 30 to April 10, and from April 27 to May 10, 2015. The weighted mean absolute difference in P falciparum prevalence in the MDA group relative to the control group was -10·6% (95% CI -15·1 to -6·1; p=0·0008) at month 3 and -4·5% (-10·9 to 1·9; p=0·14) at month 10. At month 3, the weighted P falciparum prevalence was 1·4% (0·6 to 3·6; 12 of 747) in the MDA group and 10·6% (7·0 to 15·6; 56 of 485) in the control group. Corresponding prevalences at month 10 were 3·2% (1·5 to 6·8; 34 of 1013) and 5·8% (2·5 to 12·9; 33 of 515). Adverse events were reported for 151 (3·6%) of 4173 treated individuals. The most common adverse events were dizziness (n=109) and rash or itching (n=20). No treatment-related deaths occurred. INTERPRETATION: In this low-transmission setting, the substantial reduction in P falciparum prevalence resulting from support of community case management was accelerated by MDA. In addition to supporting community health worker case management and LLIN distribution, malaria elimination programmes should consider using MDA to reduce P falciparum prevalence rapidly in foci of higher transmission. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria.

Interactions of primaquine and chloroquine with PEGylated phosphatidylcholine liposomes.

This study aimed to analyze the interaction of primaquine (PQ), chloroquine (CQ), and liposomes to support the design of optimal liposomal delivery for hepatic stage malaria infectious disease. The liposomes were composed of hydrogenated soybean phosphatidylcholine, cholesterol, and distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethyleneglycol]-2000), prepared by thin film method, then evaluated for physicochemical and spectrospic characteristics. The calcein release was further evaluated to determine the effect of drug co-loading on liposomal membrane integrity. The results showed that loading PQ and CQ into liposomes produced changes in the infrared spectra of the diester phosphate and carbonyl ester located in the polar part of the phospholipid, in addition to the alkyl group (CH2) in the nonpolar portion. Moreover, the thermogram revealed the loss of the endothermic peak of liposomes dually loaded with PQ and CQ at 186.6 °C, which is identical to that of the phospholipid. However, no crystallinity changes were detected through powder X-ray diffraction analysis. Moreover, PQ, with either single or dual loading, produced the higher calcein release profiles from the liposomes than that of CQ. The dual loading of PQ and CQ tends to interact with the polar head group of the phosphatidylcholine bilayer membrane resulted in an increase in water permeability of the liposomes.

Evaluation of the effect of supervised anti-malarial treatment on recurrences of Plasmodium vivax malaria.

BACKGROUND: Relapses in vivax malaria have posed great challenges for malaria control, and they also account for a great proportion of reported cases. Knowing the real effectiveness of a 7-day primaquine (PQ) scheme is crucial in order to evaluate not only the cost-effectiveness of implementing new anti-hypnozoite drugs, but also how health education strategies can guarantee better compliance and be reinforced. This study aimed to evaluate the effect of daily treatment with chloroquine and PQ supervised by health workers versus prescription without supervision. METHODS: The outcome was the passive detection of new positive thick blood smears up to 180 days, based on the official data records from the National Malaria Control Programme. The recurrences seen in the real life were, therefore, used as a surrogate for true relapses. RESULTS: Patients under supervised treatment had a lower risk of recurrence up to day 180 when compared to the unsupervised treatment (17.9% vs. 36.1%; p = 0.027). CONCLUSIONS: The lack of supervision in the non-supervised group (which followed standard of care in the real life) enabled proper comparison, as consent itself would have lead to greater compliance in this group. Future studies should scale such an analysis to different settings in the Brazilian Amazon.

Evaluation of pharmacokinetics of single-dose primaquine in undernourished versus normally nourished children diagnosed with Plasmodium vivax malaria in Mumbai.

BACKGROUND: The pharmacokinetics of primaquine [PQ] have been the subject of studies in both adults and healthy participants. However, there is no study on its pharmacokinetics in a setting of undernourishment. In India, there is evidence to show considerable malnourishment in children that in turn can affect drug pharmacokinetics. Given that the country is moving towards malaria elimination, the present study was planned with the objective of comparing pharmacokinetics of the drug in undernourished children relative to normally nourished children. MATERIALS AND METHODS: After Institutional Ethics Committee approval, children of either gender between the ages of 5 and 12 years and smear-positive for Plasmodium vivax malaria were included. Nourishment status was determined using the Indian Academy of Pediatrics classification of protein energy malnutrition based on Khadilkar's growth charts. Twelve children each were enrolled in the two groups. PQ was given in the dose of 0.3 mg/kg/d and blood collections were made at 0, 1, 2, 3, 4, 6, 8 and 24 hours post-dosing. Levels were estimated by high-performance liquid chromatography. Chloroquine in the dose of 25 mg/kg was given over three days along with supportive care. RESULTS: Of the 24 children, there were 17 boys and 7 girls. There was a statistically significant difference in the body weight between the undernourished and the normally nourished children [21.5 ± 5.52 vs. 28.8 ± 8.84, P < 0.05]. PQ levels showed wide inter-individual variation in both groups. No significant difference was seen in any pharmacokinetic parameter between the two groups. DISCUSSION: This study adds to the limited body of evidence on the pharmacokinetics of PQ in children with malaria and indicates that the dosing of primaquine could potentially be independent of the nourishment status.

PHARMACOKINETICS OF PRIMAQUINE PHOSPHATE AFTER A SINGLE ORAL ADMINISTRATION TO AFRICAN PENGUINS (SPHENISCUS DEMERSUS).

Primaquine is an 8-aminoquinolone drug commonly used for the chemoprophylaxis and treatment of avian malarial infections in managed penguin populations worldwide. Little is known about its pharmacokinetic properties in avian species. The objective of this study was to describe the disposition of primaquine phosphate after a single oral dose in 15 healthy African penguins (Spheniscus demersus). A single tablet containing 26.3 mg of primaquine phosphate (equivalent to 15 mg primaquine base) was administered orally to each bird in a herring fish. Blood samples were collected prior to drug administration and at predetermined timepoints through 144 hr postadministration. Plasma was analyzed for drug concentration by high-performance liquid chromatography with ultraviolet detection. Mean maximum plasma concentration of primaquine phosphate was 277 ± 96 ng/ml at approximately 3.1 hr following oral administration. The mean disappearance half-life was 3.6 ± 1.6 hr. Plasma concentrations were below detectable limits in all but one penguin by 36 hr. A single oral administration of 26.3 mg of primaquine phosphate in African penguins resulted in a pharmacokinetic profile comparable to those attained in human studies. These results suggest that a dosing interval similar to human regimens may be of potential use in the prevention and treatment of avian malaria in penguins. Additional clinical studies are needed to determine the efficacy and safety of this regimen.

Antimalarial primaquine for skin infiltration analgesia in rats.

OBJECTIVES: The purpose of this study was to estimate the ability of antimalarial medications to induce local infiltration analgesia. METHODS: Using a rat model of skin infiltration anaesthesia, the effects of antimalarial medications (primaquine, chloroquine, hydroxychloroquine and amodiaquine) were compared with the application of lidocaine. KEY FINDINGS: At a dose of 3 µmol, primaquine and chloroquine displayed better potency (all P < 0.05) and greater duration (all P < 0.01) of cutaneous analgesia than lidocaine, whereas the other antimalarial medications showed a similar potency and duration of cutaneous analgesia when compared with lidocaine. When a dose of 3 µmol antimalarial medication was used, primaquine was the most potent and had the longest duration of action among four antimalarial medications. The relative potency ranking (ED50, 50% effective dose) has been found to be primaquine [2.10 (1.87 - 2.37) µmol] > lidocaine [6.27 (5.32 -7.39) µmol] (P < 0.01). Infiltration analgesia of skin with primaquine had a greater duration of action than did lidocaine on the equipotent (ED25, ED50, ED75) basis (P < 0.01). CONCLUSIONS: Primaquine and chloroquine have greater potency and longer lasting skin analgesia when compared with lidocaine, while the other antimalarials display a similar potency in comparison with lidocaine.

Towards one standard treatment for uncomplicated Plasmodium falciparum and Plasmodium vivax malaria: Perspectives from and for the Peruvian Amazon.

Malaria continues to wreak havoc in the Peruvian Amazon. Lengthy research efforts have brought important lessons on its particular epidemiology: the heterogeneous levels of transmission, the large reservoir of both asymptomatic and submicroscopic infections, the co-transmission of Plasmodium vivax and Plasmodium falciparum in the same areas, and the limitations of current diagnostics. Based on these features, the national elimination program could greatly benefit from simplified standard treatment, with the use of artemisinin-based combination therapy and even shorter schemes of primaquine maintaing the total dosing. It is acknowledged that there is some uncertainty regarding the true prevalence of glucose-6-phosphate dehydrogenase deficiency (G6PD) and genetic polymorphisms related to cytochrome P-450 isozyme 2D6 functioning. Once we have a better understanding, tafenoquine, whether or not in combination with a rapid G6PD enzyme test, may become a future pathway to eliminate the otherwise hidden reservoir of the P. vivax hypnozoite through one standard Plasmodium treatment.

Tafenoquine for preventing relapse in people with Plasmodium vivax malaria.

BACKGROUND: Plasmodium vivax malaria has a persistent liver stage that causes relapse of the disease and continued P vivax transmission. Primaquine (PQ) is used to clear the liver stage of the parasite, but treatment is required for 14 days. Primaquine also causes haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Tafenoquine (TQ) is a new alternative to PQ with a longer half-life and can be used as a single-dose treatment. OBJECTIVES: To assess the effects of tafenoquine 300 mg (single dose) on preventing P vivax relapse. SEARCH METHODS: We searched the following up to 3 June 2020: the Cochrane Infectious Diseases Group Specialized Register; CENTRAL; MEDLINE; Embase; and three other databases. We also searched the WHO International Clinical Trial Registry Platform and the metaRegister of Controlled Trials for ongoing trials using "tafenoquine" and "malaria" as search terms up to 3 June 2020. SELECTION CRITERIA: Randomized controlled trials (RCTs) that gave TQ to prevent relapse in people with P vivax malaria. We planned to include trials irrespective of whether participants had been screened for G6PD enzyme deficiency. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data and assessed risk of bias. As true relapse and reinfection are difficult to differentiate in people living in endemic areas, studies report "recurrences" of infection as a proxy for relapse. We carried out meta-analysis where appropriate, and gave estimates as risk ratios (RR) with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Three individually randomized RCTs met our inclusion criteria, all in endemic areas, and thus reporting recurrence. Trials compared TQ with PQ or placebo, and all participants received chloroquine (CQ) to treat the asexual infection). In all trials, pregnant and G6PD-deficient people were excluded. Tafenoquine 300 mg single dose versus no treatment for relapse prevention Two trials assessed this comparison. TQ 300 mg single dose reduces P vivax recurrences compared to no antihypnozoite treatment during a six-month follow-up, but there is moderate uncertainty around effect size (RR 0.32, 95% CI 0.12 to 0.88; 2 trials, 504 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (2 trials, 504 participants; moderate-certainty evidence). However, we are uncertain if TQ causes more serious adverse events (2 trials, 504 participants; very low-certainty evidence). Both RCTs reported a total of 23 serious adverse events in TQ groups (One RCT reported 21 events) and a majority (15 events) were a drop in haemoglobin level by > 3g/dl (or >30% reduction from baseline). Tafenoquine 300 mg single dose versus primaquine 15 mg/day for 14 days for relapse prevention Three trials assessed this comparison. There is probably little or no difference between TQ and PQ in preventing recurrences (proxy measure for relapse) up to six months of follow-up (RR 1.04, 95% CI 0.8 to 1.34; 3 trials, 747 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (3 trials, 747 participants; moderate-certainty evidence). We are uncertain if TQ can cause more serious adverse events compared to PQ (3 trials, 747 participants; very low-certainty evidence). Two trials had higher point estimates against TQ while the other showed the reverse. Most commonly reported serious adverse event in TQ group was a decline in haemoglobin level (19 out of 29 events). Some other serious adverse events, though observed in the TQ group, are unlikely to be caused by it (Hepatitis E infection, limb abscess, pneumonia, menorrhagia). AUTHORS' CONCLUSIONS: TQ 300 mg single dose prevents relapses after clinically parasitologically confirmed P vivax malaria compared to no antihypnozoite treatment, and with no difference detected in studies comparing it to PQ to date. However, the inability to differentiate a true relapse from a recurrence in the available studies may affect these estimates. The drug is untested in children and in people with G6PD deficiency. Single-dose treatment is an important practical advantage compared to using PQ for the same purpose without an overall increase in adverse events in non-pregnant, non-G6PD-deficient adults.

Primaquine alternative dosing schedules for preventing malaria relapse in people with Plasmodium vivax.

BACKGROUND: Plasmodium vivax liver stages (hypnozoites) may cause relapses, prolonging morbidity, and impeding malaria control and elimination. The World Health Organization (WHO) recommends three schedules for primaquine: 0.25 mg/kg/day (standard), or 0.5 mg/kg/day (high standard) for 14 days, or 0.75 mg/kg once weekly for eight weeks, all of which can be difficult to complete. Since primaquine can cause haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, clinicians may be reluctant to prescribe primaquine without G6PD testing, and recommendations when G6PD status is unknown must be based on an assessment of the risks and benefits of prescribing primaquine. Alternative safe and efficacious regimens are needed. OBJECTIVES: To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high-standard 14-day courses. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); LILACS (BIREME); WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 2 September 2019, and checked the reference lists of all identified studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) of adults and children with P vivax malaria using either chloroquine or artemisinin-based combination therapy plus primaquine at a total adult dose of at least 210 mg, compared with the WHO-recommended regimens of 0.25 or 0.5 mg/kg/day for 14 days. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow-up, partner drug, and trial location. We analysed safety data where included. MAIN RESULTS: 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six to seven months when using the same total dose (210 mg adult dose) over seven days compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 4 RCTs, 1211 participants; low-certainty evidence). No serious adverse events were reported. We do not know if there is any difference in the number of adverse events resulting in discontinuation of primaquine (RR 1.04, 95% CI 0.15 to 7.38; 5 RCTs, 1427 participants) or in the frequency of anaemia (RR 3.00, 95% CI 0.12 to 72.91, 1 RCT, 240 participants) between the shorter and longer regimens (very low-certainty evidence). Three trials excluded people with G6PD deficiency; two did not provide this information. Pregnant and lactating women were either excluded or no details were provided. High-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six months with 0.5 mg/kg/day primaquine for 14 days compared to 0.25 mg/kg/day for 14 days (RR 0.84 (95% CI 0.49 to 1.43; 2 RCTs, 677 participants, low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events resulting in discontinuation of treatment with the high-standard dosage (RR 4.19, 95% CI 0.90 to 19.60; 1 RCT, 778 participants, very low-certainty evidence). People with G6PD deficiency and pregnant or lactating women were excluded. 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to high-standard 0.5 mg/kg/day for 14 days, at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.60; 1 RCT, 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. G6PD-deficient patients were not randomized but included in the weekly primaquine group (only one patient detected). 1 mg/kg/day for seven days versus high standard 0.5 mg/kg/day for 14 days There is probably little or no difference in P vivax recurrences at 12 months between 1.0 mg/kg/day primaquine for seven days and the high-standard 0.5 mg/kg/day for 14 days (RR 1.03, 95% CI 0.82 to 1.30; 2 RCTs, 2526 participants; moderate-certainty evidence). There may be moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for seven days compared with the high-standard 0.5 mg/kg/day for 14 days, during 42 days follow-up (RR 12.03, 95% CI 1.57 to 92.30; 1 RCT, 1872 participants, low-certainty evidence). We do not know if there is a difference between 1.0 mg/kg/day primaquine for seven days and high-standard 0.5 mg/kg/day for 14 days in adverse events that resulted in discontinuation of treatment (RR 2.50, 95% CI 0.49 to 12.87; 1 RCT, 2526 participants, very low-certainty evidence), nor if there is difference in frequency of anaemia by 42 days (RR 0.93, 95% CI 0.62 to 1.41; 2 RCTs, 2440 participants, very low-certainty evidence). People with G6PD deficiency were excluded. Other regimens Two RCTs evaluated other rarely-used doses of primaquine, one of which had very high loss to follow-up. Adverse events were not reported. People with G6PD deficiency and pregnant or lactating women were excluded. AUTHORS' CONCLUSIONS: Trials available to date do not detect a difference in recurrence between the following regimens: 1) 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days; 2) high-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days; 3) 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days; 4) 1 mg/kg/day for seven days versus high-standard 0.5 mg/kg/day for 14 days. There were no differences detected in adverse events for Comparisons 1, 2 or 3, but there may be more serious adverse events with the high seven-day course in Comparison 4. The shorter regimen of 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days may suit G6PD-normal patients. Further research will help increase the certainty of the findings and applicability in different settings.

Quantifying and preventing Plasmodium vivax recurrences in primaquine-untreated pregnant women: An observational and modeling study in Brazil.

Each year, 4.3 million pregnant women are exposed to malaria risk in Latin America and the Caribbean. Plasmodium vivax causes 76% of the regional malaria burden and appears to be less affected than P. falciparum by current elimination efforts. This is in part due to the parasite's ability to stay dormant in the liver and originate relapses within months after a single mosquito inoculation. Primaquine (PQ) is routinely combined with chloroquine (CQ) or other schizontocidal drugs to supress P. vivax relapses and reduce the risk of late blood-stage recrudescences of parasites with low-grade CQ resistance. However, PQ is contraindicated for pregnant women, who remain at increased risk of repeated infections following CQ-only treatment. Here we apply a mathematical model to time-to-recurrence data from Juruá Valley, Brazil's main malaria transmission hotspot, to quantify the extra burden of parasite recurrences attributable to PQ ineligibility in pregnant women. The model accounts for competing risks, since relapses and late recrudescences (that may be at least partially prevented by PQ) and new infections (that are not affected by PQ use) all contribute to recurrences. We compare recurrence rates observed after primary P. vivax infections in 158 pregnant women treated with CQ only and 316 P. vivax infections in non-pregnant control women, matched for age, date of infection, and place of residence, who were administered a standard CQ-PQ combination. We estimate that, once infected with P. vivax, 23% of the pregnant women have one or more vivax malaria recurrences over the next 12 weeks; 86% of these early P. vivax recurrences are attributable to relapses or late recrudescences, rather than new infections that could be prevented by reducing malaria exposure during pregnancy. Model simulations indicate that weekly CQ chemoprophylaxis extending over 4 to 12 weeks, starting after the first vivax malaria episode diagnosed in pregnancy, might reduce the risk of P. vivax recurrences over the next 12 months by 20% to 65%. We conclude that post-treatment CQ prophylaxis could be further explored as a measure to prevent vivax malaria recurrences in pregnancy and avert their adverse effects on maternal and neonatal health.

Doses of primaquine administered to children with Plasmodium vivax according to an age-based dose regimen.

Primaquine is still the first-line drug to eliminate hypnozoites of Plasmodium vivax. The therapeutic efficacy is related to the total dose administered. In several endemic areas, the drug is administered for children in an age-based regimen, which can lead to inadequate exposure, increasing the rates of recurrence of the infection. The present study aims to describe the mg/kg total dose of primaquine administered to children for treatment for vivax malaria when an age-based regimen is used and to measure the plasma concentrations of primaquine and carboxyprimaquine. A total of 85 children were included in the study. The total dose of primaquine administered based on mg/kg had a median value of 3.22 mg/kg. The percentage of patients with a total dose below the required dose of 3.5 mg/kg was 55.75%. The median primaquine maximum concentration was 94 ng/ml. For carboxy-primaquine, the median maximum concentration was 375 ng/ml. The results suggest that age-based dosing regimens likely lead to substantial under-dosing of primaquine, which is evident in the youngest children and is reflected in decreased levels of primaquine and carboxy-primaquine in plasma samples 13.