1. Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials
- Author
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Bastiaens, Guido J. H., Tiono, Alfred B., Okebe, Joseph, Pett, Helmi E., Coulibaly, Sam A., Goncalves, Bronner P., Affara, Muna, Ouedraogo, Alphonse, Bougouma, Edith C., Sanou, Guillaume S., Nebie, Issa, Bradley, John, Lanke, Kjerstin H. W., Niemi, Mikko, Sirima, Sodiomon B., d'Alessandro, Umberto, Bousema, Teun, Drakeley, Chris, Clinicum, Department of Clinical Pharmacology, Medicum, University of Helsinki, and HUSLAB
- Subjects
TRANSMISSION ,lcsh:R ,REDUCE GAMETOCYTE CARRIAGE ,PLASMODIUM-VIVAX MALARIA ,lcsh:Medicine ,CHILDREN ,G6PD DEFICIENCY ,DOUBLE-BLIND ,ARTEMETHER-LUMEFANTRINE ,3121 General medicine, internal medicine and other clinical medicine ,parasitic diseases ,lcsh:Q ,3111 Biomedicine ,DIHYDROARTEMISININ-PIPERAQUINE ,CYP 2D6 ,lcsh:Science ,DRUG DEVELOPMENT - Abstract
BACKGROUND: Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria. METHODS AND FINDINGS: In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined. In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ. CONCLUSIONS: Single low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02174900 Clinicaltrials.gov NCT02654730.
- Published
- 2018