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Novel methods were proposed for determining primaquine (PQN) in tablets by multiple‐injection capillary zone electrophoresis (MI‐CZE) and by short‐end injection CZE (SEI‐CZE), both with ultraviolet detection. The background electrolyte (BGE), consisting of 20 mmol/L of tris (hydroxymethyl) aminomethane and 30 mmol/L of hydrochloric acid at pH 2.0, was selected considering a comprehensive study involving the effective mobility versus pH curves of the analytes and BGE components. Experimental designs were applied in methods developments, showing the chemometric tool's applicability in achieving suitable electrophoretic conditions. A baseline resolution in the separation of adjacent peak pairs was obtained by injecting a spacer electrolyte for 18 s, with a voltage of + 15 kV, and the sample can be injected six consecutive times in a single run in less than 3 min, in the MI‐CZE method. For the SEI‐CZE method, the migration time of PQN was 0.6 min, and the method was applied to a demonstrative forced degradation study. Some validation parameters were evaluated for both methods, and all results were satisfactory, indicating that they can be implemented as PQN determination methods in routine quality control analyses. [ABSTRACT FROM AUTHOR]

Background: Plasmodium vivax is the second most common malaria parasite in Ethiopia. It has been treated with chloroquine (CQ) for the past seven decades. However, the emergence of CQ-resistant strains in the nation urged the Federal Ministry of Health of Ethiopia to review its national malaria treatment guideline in 2018. In the revised guideline, the first-line treatment for uncomplicated P. vivax infection is a combination of CQ and primaquine (PQ). Thus, the present study was designed to evaluate the in vivo efficacy of CQ and PQ combination therapy against clinical P. vivax mono-infection in one of the malaria-endemic areas of Ethiopia. Methods: An open-label prospective clinical trial was conducted in the Limmu Kossa District, Jimma zone, Southwest Ethiopia, from September 2023 to March 2024. A total of 108 patients were recruited for the study. All participants received treatment with CQ at a dosage of 25 mg/kg over three days, followed by PQ at 0.25 mg/kg for 14 consecutive days. Patients were monitored for 42 days for any signs of treatment failure and malaria clinical symptoms, as per the World Health Organization (WHO) guidelines for anti-malarial drug evaluation. Additionally, haemoglobin (Hb) levels, body temperature, any adverse events, and signs of haemolysis were assessed. Data was analysed using R-software (version 4.0.0) and a significant level was considered at p < 0.05. Results: The median age of the patients was 23 years, ranging from 2.5 to 62 years. Of the 108 patients initially recruited, 100 completed the 42-day follow-up period. The combination therapy of CQ and PQ for uncomplicated clinical P. vivax malaria demonstrated excellent therapeutic efficacy, with a 100% cure rate observed at both day 28 and day 42. Additionally, the recommended low dose of PQ (0.25 mg/kg) was well-tolerated, with no signs of. Additionally, most common malaria symptoms were disappeared early in the follow-up period. Conclusion: The combination of CQ plus PQ has exhibited excellent efficacy against uncomplicated P. vivax malaria mono-infections. To preserve this efficacy, it is critical to ensure patients adhere to the full course of PQ treatment, despite its extended duration. Therefore, health authorities should put emphasis on the boosting of the public on the importance of finishing the prescribed medication regimen. [ABSTRACT FROM AUTHOR]

Abstract Background Plasmodium vivax is the second most common malaria parasite in Ethiopia. It has been treated with chloroquine (CQ) for the past seven decades. However, the emergence of CQ-resistant strains in the nation urged the Federal Ministry of Health of Ethiopia to review its national malaria treatment guideline in 2018. In the revised guideline, the first-line treatment for uncomplicated P. vivax infection is a combination of CQ and primaquine (PQ). Thus, the present study was designed to evaluate the in vivo efficacy of CQ and PQ combination therapy against clinical P. vivax mono-infection in one of the malaria-endemic areas of Ethiopia. Methods An open-label prospective clinical trial was conducted in the Limmu Kossa District, Jimma zone, Southwest Ethiopia, from September 2023 to March 2024. A total of 108 patients were recruited for the study. All participants received treatment with CQ at a dosage of 25 mg/kg over three days, followed by PQ at 0.25 mg/kg for 14 consecutive days. Patients were monitored for 42 days for any signs of treatment failure and malaria clinical symptoms, as per the World Health Organization (WHO) guidelines for anti-malarial drug evaluation. Additionally, haemoglobin (Hb) levels, body temperature, any adverse events, and signs of haemolysis were assessed. Data was analysed using R-software (version 4.0.0) and a significant level was considered at p

Abstract Plasmodium vivax malaria remains a global health challenge, with approximately 6.9 million estimated cases in 2022. The parasite has a dormant liver stage, the hypnozoite, which reactivates to cause repeated relapses over weeks, months, or years. These relapses erode patient health, contribute to the burden of malaria, and promote transmission. Radical cure to prevent relapses requires administration of an 8-aminoquinoline, either primaquine or tafenoquine. However, malaria treatment guidelines updated by the World Health Organization (WHO) in October 2023 restrict primaquine use for women breastfeeding children

Abstract Background To interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency. Methods An observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone. Results A total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28–15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to − 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (− 0.60 g/dL) than in the G6PDd ACT alone group (− 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = − 0.00 to 0.20) and 0.05 g/dl (95% CI = − 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412). Conclusions This study’s findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patient's G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes.

Abstract Background Plasmodium vivax malaria is still an important public health problem in Ethiopia. Unlike Plasmodium falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine. Drug resistance to chloroquine is threatening malaria control and elimination efforts. This study assessed the therapeutic efficacy and safety of chloroquine plus 14 days of primaquine on P. vivax infection based on parasitological, clinical, and haematological parameters. Methods A single-arm in vivo prospective therapeutic efficacy study was conducted to assess the clinical and parasitological response to the first-line treatment of P. vivax in Ethiopia, chloroquine plus 14 days low dose of (0.25 mg/kg/day) primaquine between December 2022 and March 2023 at Hamusit Health Centre using the standard World Health Organization (WHO) protocol. A total of 100 study participants with P. vivax mono-infection who were over 6 months old were enrolled and monitored for adequate clinical and parasitological responses for 42 days. The WHO double-entry Excel sheet and SPSS v.25 software were used for Kaplan–Meier survival analysis, and a paired t-test was used for analysis of haemoglobin improvements between follow up days. Results A total of 100 patients were enrolled among those, 96% cases were rural residents, 93% had previous malaria exposure, and predominant age group was 5–15 years (61%). 92.6% (95% CI 85.1–96.4%) of enrolled patients were adequate clinical and parasitological response, and 7.4% (95% CI 3.6–14.9%) recurrences were observed among treated patients. The fever and parasite clearance rate on day 3 were 98% and 94%, respectively. The baseline haemoglobin levels improved significantly compared to those days 14 and 42 (p

Plasmodium vivax malaria remains a global health challenge, with approximately 6.9 million estimated cases in 2022. The parasite has a dormant liver stage, the hypnozoite, which reactivates to cause repeated relapses over weeks, months, or years. These relapses erode patient health, contribute to the burden of malaria, and promote transmission. Radical cure to prevent relapses requires administration of an 8-aminoquinoline, either primaquine or tafenoquine. However, malaria treatment guidelines updated by the World Health Organization (WHO) in October 2023 restrict primaquine use for women breastfeeding children < 6 months of age, or women breastfeeding older children if their child is G6PD deficient or if the child's G6PD status is unknown. Primaquine restrictions assume that 8-aminoquinoline exposures in breast milk would be sufficient to cause haemolysis in the nursing infant should they be G6PD deficient. WHO recommendations for tafenoquine are awaited. Notably, the WHO recommends that infants are breastfed for the first 2 years of life, and exclusively until 6 months old. Repeated pregnancies, followed by extended breastfeeding leaves women in P. vivax endemic regions potentially vulnerable to relapses for many years. This puts women's health at risk, increases the malaria burden, and perpetuates transmission, hindering malaria control and elimination. The benefits of lifting restrictions on primaquine administration to breastfeeding women are significant, avoiding the adverse consequences of repeated episodes of acute malaria, such as severe anaemia. Recent data challenge the restriction of primaquine in breastfeeding women. Clinical pharmacokinetic data in breastfeeding infants ≥ 28 days old show that the exposure to primaquine is very low and less than 1% of the maternal exposure, indicating negligible risk to infants, irrespective of their G6PD status. Physiologically-based pharmacokinetic modelling complements the clinical data, predicting minimal primaquine exposure to infants and neonates via breast milk from early post-partum. This article summarizes the clinical and modelling evidence for a favourable benefit:risk evaluation of P. vivax radical cure with primaquine for breastfeeding women without the need for infant G6PD testing, supporting a change in policy. This adjustment to current treatment guidelines would support health equity in regard to effective interventions to protect women and their children, enhance malaria control strategies, and advance P. vivax elimination. [ABSTRACT FROM AUTHOR]

Background: Radical cure of Plasmodium vivax infections is key to the control of vivax malaria. However, the standard doses of 8-aminoquinoline drugs used for radical cure can cause severe haemolysis in G6PD-deficient patients. The availability of near-patient G6PD tests could increase use of primaquine (PQ), however direct evidence of the impacts that G6PD testing has on downstream patient outcomes, such as haemolysis and recurrence is lacking. Methodology/Principle findings: A linked-evidence model was created to investigate changes in the number of severe haemolysis events and P. vivax recurrences within 6 months of treatment when qualitative G6PD testing was used to guide PQ treatment (0.25mg/kg/day for 14 days and 0.5mg/kg/day for 7 days), compared to prescribing 14-day PQ with no G6PD testing. In the model patients identified as G6PD-deficient received 8-week PQ (0.75mg/kg/week). The model was used to simulate scenarios with 1%, 5% and 10% prevalence of G6PD-deficiency (G6PDd) in theoretical populations of 10,000 male and female P. vivax patients and initially assumed 100% adherence to the prescribed PQ regiment. Results illustrate that G6PD testing to guide the 14-day PQ regiment reduced severe haemolysis by 21–80% and increased recurrences by 3–6%, compared to applying the 14-day PQ regiment without G6PD testing. Results for the 7-day PQ regiment informed by G6PD testing were mixed, dependent on G6PDd prevalence and sex. When adherence to the PQ regiments was less than perfect the model predicted reductions in the number of recurrences at all prevalence levels, provided adherence to 7-day PQ was 5–10% higher than adherence to the 14-day regiment. Conclusions/Significance: Introduction of G6PD testing to guide PQ treatment reduces severe haemolysis events for the 14-day regiment, and the 7-day regiment in higher G6PDd prevalence settings, compared to use of 14-day PQ without G6PD testing when all patients adhere to the prescribed PQ treatment. At a population level, there were increases in recurrences, but this could be resolved when the 7-day regiment was used and had superior adherence compared to the 14-day regiment. Author summary: To eliminate vivax malaria treatment is required that cures the blood infection and also kills any dormant parasites in the liver (called hypnozoites). Unfortunately, drugs currently available to treat hypnozoites such as primaquine can cause severe haemolysis when given to patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common human enzyme polymorphism. The author created a mathematical model that compares the number of severe haemolysis events and vivax recurrences within 6 months of treatment in a theoretical population when qualitative G6PD tests are used to guide primaquine treatment versus the use of primaquine without consideration of the G6PD status of the patient. The results demonstrate that adding G6PD tests into the clinical pathway can reduce the number of severe haemolysis events, but may increase the number of recurrences, with specific results determined by the prevalence of G6PD deficiency, the dosing regiment and adherence to the prescribed primaquine treatment. [ABSTRACT FROM AUTHOR]

AbstractPrimaquine (PQ) is a widely used antimalarial drug, but its high dosage requirements can lead to significant tissue damage and adverse gastrointestinal and hematological effects. Recent studies have shown that nanoformulations can enhance the bioavailability of pharmaceuticals, thereby increasing efficacy, reducing dosing frequency, and minimizing toxicity. In this study, PQ-loaded PLGA nanoparticles (PQ-NPs) were prepared using a modified double emulsion solvent evaporation technique (w/o/w). The PQ-NPs exhibited a mean particle size of 228 ± 2.6 nm, a zeta potential of +27.4 mV, and an encapsulation efficiency of 81.3 ± 3.5%. Scanning electron microscopy (SEM) confirmed their spherical morphology, and the in vitro release profile demonstrated continuous drug release over 72 h. Differential scanning calorimetry (DSC) thermograms indicated that the drug was present in the nanoparticles, with improved physical stability. Fourier-transform infrared spectroscopy (FTIR) analysis showed no interactions between the various substances in the NPs. In vivo studies in Swiss albino mice infected with Plasmodium berghei revealed that the nanoformulated PQ was 20% more effective than the standard oral dose. Biodistribution studies indicated that 80% of the NPs accumulated in the liver, highlighting their potential for targeted drug delivery. This research demonstrates the successful development of a nanomedicine delivery system for antimalarial drugs, offering a promising strategy to enhance treatment efficacy while reducing adverse effects. [ABSTRACT FROM AUTHOR]

Background: To interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency. Methods: An observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone. Results: A total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28–15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to − 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (− 0.60 g/dL) than in the G6PDd ACT alone group (− 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = − 0.00 to 0.20) and 0.05 g/dl (95% CI = − 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412). Conclusions: This study's findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patient's G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes. [ABSTRACT FROM AUTHOR]

Background: Plasmodium vivax malaria is still an important public health problem in Ethiopia. Unlike Plasmodium falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine. Drug resistance to chloroquine is threatening malaria control and elimination efforts. This study assessed the therapeutic efficacy and safety of chloroquine plus 14 days of primaquine on P. vivax infection based on parasitological, clinical, and haematological parameters. Methods: A single-arm in vivo prospective therapeutic efficacy study was conducted to assess the clinical and parasitological response to the first-line treatment of P. vivax in Ethiopia, chloroquine plus 14 days low dose of (0.25 mg/kg/day) primaquine between December 2022 and March 2023 at Hamusit Health Centre using the standard World Health Organization (WHO) protocol. A total of 100 study participants with P. vivax mono-infection who were over 6 months old were enrolled and monitored for adequate clinical and parasitological responses for 42 days. The WHO double-entry Excel sheet and SPSS v.25 software were used for Kaplan–Meier survival analysis, and a paired t-test was used for analysis of haemoglobin improvements between follow up days. Results: A total of 100 patients were enrolled among those, 96% cases were rural residents, 93% had previous malaria exposure, and predominant age group was 5–15 years (61%). 92.6% (95% CI 85.1–96.4%) of enrolled patients were adequate clinical and parasitological response, and 7.4% (95% CI 3.6–14.9%) recurrences were observed among treated patients. The fever and parasite clearance rate on day 3 were 98% and 94%, respectively. The baseline haemoglobin levels improved significantly compared to those days 14 and 42 (p < 0.001). No serious adverse event was observed during the study period. Conclusions: In this study, co-administration of chloroquine with primaquine was efficacious and well-tolerated with fast resolution of fever and high parasites clearance rate. However, the 7.4% failure is reported is alarming that warrant further monitoring of the therapeutic efficacy study of P. vivax. [ABSTRACT FROM AUTHOR]

BackgroundIndia accounts for the bulk of Plasmodium vivax burden in South East Asia. Primaquine (PQ) is the only currently available drug for treating relapses in P. vivax malaria. MethodsHere, we provide an overview of the epidemiology and clinical characteristics of P. vivax recurrent infections in India and discuss current knowledge gaps and priority research areas for further investigations, with emphasis on relapses and their radical cure with PQ. Results and discussionA total of 27 studies involving ~27,000 P. vivax infected patients were finally included. Recurrent infections with P. vivax malaria are common, especially in young males. The burden of P. vivax relapse greatly varies across Indian regions, with a proportion range of 1.47 to 6% based on the included studies which all used low (very low) PQ dose. There is a need for more empirical data on the effectiveness and safety of weekly administration of PQ at 0.75 mg/Kg for eight weeks in G6PD–deficiency patients in India, especially in children. Further research priorities should also be focused on the epidemiology of confounding factor, such as CQ-resistance, mixed infections, or Pv genetic diversity are needed. The clinical impact of P. vivax relapses (e.g., severe malaria, mortality) is also of valuable interest in upcoming studies. More studies addressing the above-mentioned missing links should be implemented to inform malariologists, clinicians, populations, and policy makers on real situation of P. vivax relapses and the clinical impact of PQ in India. All taken together, these would have important implications for P. vivax malaria control and elimination in endemic areas.

Abstract Background With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. Methods A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (C max) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%. Results 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM C max values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for C max and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. Conclusion IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699

Abstract 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

Abstract Background Plasmodium vivax relapses due to dormant liver hypnozoites can be prevented with primaquine. However, the dose must be adjusted in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency. In French Guiana, assessment of G6PD activity is typically delayed until day (D)14 to avoid the risk if misclassification. This study assessed the kinetics of G6PD activity throughout P. vivax infection to inform the timing of treatment. Methods For this retrospective monocentric study, data on G6PD activity between D1 and D28 after treatment initiation with chloroquine or artemisinin-based combination therapy were collected for patients followed at Cayenne Hospital, French Guiana, between January 2018 and December 2020. Patients were divided into three groups based on the number of available G6PD activity assessments: (i) at least two measurements during the P. vivax malaria infection; (ii) two measurements: one during the current infection and one previously; (iii) only one measurement during the malaria infection. Results In total, 210 patients were included (80, 20 and 110 in groups 1, 2 and 3, respectively). Data from group 1 showed that G6PD activity remained stable in each patient over time (D1, D3, D7, D14, D21, D28). None of the patients with normal G6PD activity during the initial phase (D1–D3) of the malaria episode (n = 44) was categorized as G6PD-deficient at D14. Patients with G6PD activity

Background: With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. Methods: A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%. Results: 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. Conclusion: IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699 [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. Brazilian Ministry of Health, Municipal and State Health Secretariats; Fiocruz; Medicines for Malaria Venture; Bill & Melinda Gates Foundation; Newcrest Mining; and the UK Government. For the Portuguese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background Antimalarial drug resistance surveillance and containment are crucial for countries aiming to eliminate malaria. Monitoring resistance evolution through studies before and after treatment policy changes is essential. Methods A total of 939 Plasmodium falciparum-positive blood samples were collected between 2014 and 2015 across 10 sites in India, categorized into 4 geographic clusters. Polymerase chain reaction-amplified products were sequenced to identify point mutations at drug resistance-conferring genes (Pfdhfr , Pfdhps , Pfmdr1, and Pfk13). Results Triple Pfdhfr mutants were found only in northeast India bordering Myanmar, while the wild type (WT) was dominant in central India. Pfdhps WTs were prevalent in all areas, and no double mutants were found. Except in northwest India, Pfmdr1 WT was dominant in all clusters. Nonsynonymous double mutations were only found in northwest India. Only synonymous mutations occurred in Pfk13. These were found in central India at a low frequency. The pattern of linkage disequilibrium and principal component analysis reflects low pressure for drug resistance and heterogeneity between the geographic clusters. Conclusions Resistance levels were highest in northeast India, close to the Myanmar border, where resistance is common. Primaquine has been widely used as a gametocidal and schizonticidal drug, likely contributing to maintaining low drug resistance levels and preventing strong selection for resistance. [ABSTRACT FROM AUTHOR]

Background Plasmodium vivax presents a significant challenge for malaria elimination in the Greater Mekong Subregion. We evaluated the effectiveness of primaquine for reducing relapses of vivax malaria. Methods Patients with uncomplicated P vivax malaria from eastern Myanmar received chloroquine (25-mg base/kg given in 3 days) plus unsupervised PQ (0.25 mg/kg/d for 14 days) without screening for glucose-6-phosphate dehydrogenase deficiency and were followed for a year. Results A total of 556 patients were enrolled to receive the chloroquine/primaquine treatment from February 2012 to August 2013. During the follow-up, 38 recurrences were detected, presenting a cumulative recurrence rate of 9.1% (95% CI, 4.1%–14.1%). Genotyping at the pvmsp1 and pvmsp3α loci by amplicon deep sequencing and model prediction indicated that 13 of the 27 recurrences with genotyping data were likely due to relapses. Notably, all confirmed relapses occurred within the first 6 months. Conclusions The unsupervised standard dose of primaquine was highly effective as a radical cure for P vivax malaria in eastern Myanmar. The high presumed effectiveness might have benefited from the health messages delivered during the enrollment and follow-up activities. Six-month follow-ups in the Greater Mekong Subregion are sufficient for detecting most relapses. [ABSTRACT FROM AUTHOR]

Background: Plasmodium vivax relapses due to dormant liver hypnozoites can be prevented with primaquine. However, the dose must be adjusted in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency. In French Guiana, assessment of G6PD activity is typically delayed until day (D)14 to avoid the risk if misclassification. This study assessed the kinetics of G6PD activity throughout P. vivax infection to inform the timing of treatment. Methods: For this retrospective monocentric study, data on G6PD activity between D1 and D28 after treatment initiation with chloroquine or artemisinin-based combination therapy were collected for patients followed at Cayenne Hospital, French Guiana, between January 2018 and December 2020. Patients were divided into three groups based on the number of available G6PD activity assessments: (i) at least two measurements during the P. vivax malaria infection; (ii) two measurements: one during the current infection and one previously; (iii) only one measurement during the malaria infection. Results: In total, 210 patients were included (80, 20 and 110 in groups 1, 2 and 3, respectively). Data from group 1 showed that G6PD activity remained stable in each patient over time (D1, D3, D7, D14, D21, D28). None of the patients with normal G6PD activity during the initial phase (D1–D3) of the malaria episode (n = 44) was categorized as G6PD-deficient at D14. Patients with G6PD activity < 80% at D1 or D3 showed normal activity at D14. Sex and reticulocyte count were statistically associated with G6PD activity variation. In the whole sample (n = 210), no patient had severe G6PD deficiency (< 10%) and only three between 10 and 30%, giving a G6PD deficiency prevalence of 1.4%. Among the 100 patients from group 1 and 2, 30 patients (26.5%) were lost to follow-up before primaquine initiation. Conclusions: In patients treated for P. vivax infection, G6PD activity did not vary over time. Therefore, G6PD activity on D1 instead of D14 could be used for primaquine dose-adjustment. This could allow earlier radical treatment with primaquine, that could have a public health impact by decreasing early recurrences and patients lost to follow-up before primaquine initiation. This hypothesis needs to be confirmed in larger prospective studies. [ABSTRACT FROM AUTHOR]