Stijn W. van Beek (1), Elin M. Svensson (1,2), Alfred Tiono (3), Joseph Okebe (4), Umberto D’Alessendro (4), Bronner Goncalves (5), Chris Drakeley (5), Teun Bousema (6), Rob ter Heine (1)
(1) Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (3) National Center for Research and Training on Malaria (CNRFP), Burkina Faso; (4) Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, The Gambia; (5) London School of Hygiene & Tropical Medicine, London, The United Kingdom (6) Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands
Introduction: Primaquine (PQ) is crucial in the treatment and prophylaxis of malaria. PQ has numerous metabolites and both efficacy and serious adverse effects have been related to them. Toxicity of PQ is aggravated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to a lowered defence against oxidative stress, sometimes causing severe hemolysis. The WHO recommends community-wide mass drug administration (MDA) of PQ in a 0.25 mg/kg single dose for areas approaching interruption of Plasmodium falciparum transmission with good access to treatment and surveillance1. The idea is that by treating the whole community, asymptomatic malaria cases are cured and do not add to transmission anymore. However, government agencies of malaria endemic countries are hesitant to implement MDA of PQ because of worries for severe hemolysis. Although a clear relationship between PQ dose and hemolysis has been established, the relationship between PQ pharmacokinetics (PK) and hemolysis has not yet been elucidated. Furthermore, it is unknown which MDA dosing strategies result in effective and safe exposures in populations with varying prevalence of G6PD deficiency.
Objective: The aim of this study was to identify the relationship between PQ PK and hemolysis and to evaluate different PQ MDA dosing regimens.
Methods: PK analysis was performed by means of nonlinear mixed-effects modelling. Single low-dose PQ PK and hemoglobin data from an adult (n=16, G6PD deficient2) and a pediatric study (n=40, G6PD normal3) were used. The PK model was based on previous work in children and extended to adults4. The relationship between PQ PK and hemolysis was modelled using an established erythrocyte lifespan model5. The developed model was used to explore the safety of PQ in a Sub-Sahara African MDA setting through Monte Carlo simulations. Anthropometric databases from Ethiopia, Namibia, Sierra Leone, Senegal, Sao Tome and Principe, Uganda and South Africa were acquired from the Demographic and Health Surveys program6. A 1000 individuals per country were randomly sampled for the simulation dataset. Distributions for CYP2D6 status and G6PD deficiency were randomly assigned to the sampled individuals according to distributions described in literature7,8. The model-derived AUC0-inf, Cmax and hemoglobin nadir were simulated for 0.25 mg/kg and 0.4 mg/kg PQ in single dose or split over day 1, 2, and 3. The predicted (severity of) anemia was assessed as measure of safety. The Cmax and AUC0-inf were used to compare the efficacy of the different dosing strategies.
Results: The PK model for PQ in children4 was successfully extended to adults by means of allometric scaling of the PK on body weight and re-estimation of the parameters. The erythrocyte lifespan model included 4 transit compartments and a concentration-slope effect describing the clearance of erythrocytes as a result of PQ-induced hemolysis. The estimated G6PD deficiency effect was a 2.4 fold increase of the PQ-induced hemolysis (RSE 88%, P<0.01). The estimated lifespan of the erythrocytes was 276 hours (RSE 40%). A single 0.25 mg/kg dose of PQ in a G6PD deficient adult typically resulted in a drop of 2.3% in hemoglobin from baseline. Anemia before treatment was common in the simulation dataset: 36.4% overall (mild, moderate and severe) and 1.6% severe. In MDA simulations, a dose of 0.4 mg/kg split over 3 days resulted in more overall anemia (41.2%) compared to a single dose of 0.25 mg/kg (39.7%). Severe anemia for 0.4 mg/kg split over 3 days (1.82%) was similar compared to 0.25 mg/kg in a single dose (1.85%). The median AUC0-inf of the 0.4 mg/kg split regimen is increased (160%) while the median Cmax is lowered (56%) compared to the 0.25 mg/kg single dose regimen which is as expected according to the linear pharmacokinetics in the model.
Conclusion: We show that a 0.4 mg/kg dose split over 3 days as opposed to the currently recommended 0.25 mg/kg single dose could result in an increased total exposure, similar severe anemia, but also a significantly lowered maximum concentration. The dosing regimen of 0.4 mg/kg split over 3 days is promising as most concerns are for occurrence of severe anemia. This encourages prospective clinical trials of efficacy and safety with this strategy. However, the lowered Cmax could be a problem as it is unclear if efficacy is AUC or Cmax dependent. The low predicted incidence of severe anemia encourages the feasibility of MDA of PQ.
References:
[1] World Health Organization. Meeting report of the WHO Evidence Review Group on mass drug administration for malaria. https://www.who.int.
[2] Bastiaens GJH, Tiono AB, Okebe J, Pett HE, Coulibaly SA, Goncalves BP, et al. Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials. PLoS One. 2018;13(1):e0190272.
[3] Goncalves BP, Tiono AB, Ouedraogo A, Guelbeogo WM, Bradley J, Nebie I, et al. Single low dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission after artemether-lumefantrine in children with asymptomatic infection: a randomised, double-blind, placebo-controlled trial. BMC Med. 2016;14:40.
[4] Goncalves, B.P., et al., Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children. Antimicrob Agents Chemother, 2017. 61(5).
[5] Lledo-Garcia R, Kalicki RM, Uehlinger DE, Karlsson MO. Modeling of red blood cell life-spans in hematologically normal populations. J Pharmacokinet Pharmacodyn. 2012;39(5):453-62.
[6] ICF. The DHS Program website. Funded by USAID. http://www.dhsprogram.com.
[7] Pett H, Bradley J, Okebe J, Dicko A, Tiono AB, Goncalves BP, et al. CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum. Antimicrobial agents and chemotherapy. 2019;63(10).
[8] Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M, et al. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med. 2012;9(11):e1001339.
Reference: PAGE () Abstr 9545 [www.page-meeting.org/?abstract=9545]
Poster: Drug/Disease Modelling - Infection