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

• Main Authors: Stijn W. van Beek, Elin M. Svensson, Alfred B. Tiono, Joseph Okebe, Umberto D’Alessandro, Bronner P. Gonçalves, Teun Bousema, Chris Drakeley, Rob ter Heine
• Format: Article
• Language: English
• Published: BMC 2021-10-01
• Series: Parasites & Vectors
• Subjects: Primaquine; Malaria; Plasmodium falciparum; Mass Drug Administration; Modeling; G6PD
• Online Access: https://doi.org/10.1186/s13071-021-05034-4

Abstract 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. Graphical abstract