title: Single Low Dose Primaquine (0.25 mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects.
abstract: BACKGROUND
  Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75 mg/kg (adult dose 45 mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15-20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25 mg/kg (adult dose 15 mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%.
  
  
  RESULTS
  The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic.
  
  
  CONCLUSIONS
  The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01872702.
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Germana
authors.initials: G
authors.lastname: Bancone
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Nongnud
authors.initials: N
authors.lastname: Chowwiwat
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Raweewan
authors.initials: R
authors.lastname: Somsakchaicharoen
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Lalita
authors.initials: L
authors.lastname: Poodpanya
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Paw Khu
authors.initials: PK
authors.lastname: Moo
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Gornpan
authors.initials: G
authors.lastname: Gornsawun
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Ladda
authors.initials: L
authors.lastname: Kajeechiwa
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: May Myo
authors.initials: MM
authors.lastname: Thwin
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Santisuk
authors.initials: S
authors.lastname: Rakthinthong
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Suphak
authors.initials: S
authors.lastname: Nosten
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Suradet
authors.initials: S
authors.lastname: Thinraow
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Slight Naw
authors.initials: SN
authors.lastname: Nyo
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Ling
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Jacher
authors.initials: J
authors.lastname: Wiladphaingern
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Naw Lily
authors.initials: NL
authors.lastname: Kiricharoen
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.|Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia.
authors.forename: Kerryn A
authors.initials: KA
authors.lastname: Moore
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000097:blood / Q000150:complications*; D006454:Hemoglobins / Q000032:analysis; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects*; D011319:Primaquine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000962:Antimalarials; D006454:Hemoglobins; D011319:Primaquine