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

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.

• 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
• Journal: Parasites & vectors (Parasit Vectors) Vol. 14 Issue 1 Pg. 524 (Oct 09 2021) ISSN: 1756-3305 [Electronic] England
• PMID: 34627346 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Antimalarials
• Drug Combinations
• Primaquine

Topics

• Adolescent
• Adult
• Africa South of the Sahara (epidemiology)
• Antimalarials (administration & dosage, pharmacokinetics)
• Child
• Child, Preschool
• Drug Combinations
• Female
• Glucosephosphate Dehydrogenase Deficiency (drug therapy, epidemiology)
• Humans
• Malaria, Falciparum (drug therapy, epidemiology, parasitology, prevention & control)
• Male
• Plasmodium falciparum (drug effects)
• Primaquine (administration & dosage, pharmacokinetics)
• Young Adult