<i>CYP2D6</i>
            Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

Pett, Helmi; Bradley, John; Okebe, Joseph; Dicko, Alassane; Tiono, Alfred B.; Gonçalves, Bronner P.; Chen, Ingrid; Lanke, Kjerstin; Neuvonen, Mikko; Mustaniemi, Anna-Liina; Gosling, Roly; D’Alessandro, Umberto; Drakeley, Chris; Niemi, Mikko; Bousema, Teun

doi:10.1128/aac.00538-19

Cited by 13 publications

(16 citation statements)

References 35 publications

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“…Individual body weight was introduced into the pharmacokinetic model as a fixed allometric function, and all other covariates (age, dose, and CYP2D6 activity score) were investigated by a stepwise addition and elimination approach. The distribution of CYP2D6 activity scores in this population has been reported elsewhere 20 …”

Section: Methodsmentioning

confidence: 80%

Mechanistic Modeling of Primaquine Pharmacokinetics, Gametocytocidal Activity, and Mosquito Infectivity

Chotsiri

Mahamar

Hoglund

et al. 2022

Clin Pharma and Therapeutics

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Clinical studies have shown that adding a single 0.25 mg base/kg dose of primaquine to standard antimalarial regimens rapidly sterilizes Plasmodium falciparum gametocytes. However, the mechanism of action and overall impact on malaria transmission is still unknown. Using data from 81 adult Malians with P. falciparum gametocytemia who received the standard dihydroartemisinin‐piperaquine treatment course and were randomized to receive either a single dose of primaquine between 0.0625 and 0.5 mg base/kg or placebo, we characterized the pharmacokinetic‐pharmacodynamic relationships for transmission blocking activity. Both gametocyte clearance and mosquito infectivity were assessed. A mechanistically linked pharmacokinetic‐pharmacodynamic model adequately described primaquine and carboxy‐primaquine pharmacokinetics, gametocyte dynamics, and mosquito infectivity at different clinical doses of primaquine. Primaquine showed a dose‐dependent gametocytocidal effect that precedes clearance. A single low dose of primaquine (0.25 mg/kg) rapidly prevented P. falciparum transmissibility.

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Section: Methodsmentioning

confidence: 80%

Mechanistic Modeling of Primaquine Pharmacokinetics, Gametocytocidal Activity, and Mosquito Infectivity

Chotsiri

Mahamar

Hoglund

et al. 2022

Clin Pharma and Therapeutics

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“…Each individual was included four times in the simulation dataset to include more combinations of CYP2D6 status and to assess the effect of inter-individual variability better. CYP2D6 AS was randomly assigned to the sampled individuals according to distributions described in the literature, resulting in probabilities of 0.026, 0.101, 0.256, 0.386, 0.209 and 0.022 for an AS of 0, 0.5, 1, 1.5, 2 and 3, respectively [ 28 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

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

Beek¹,

Svensson

Tiono

et al. 2021

Parasites Vectors

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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

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“…The RBC concentration of o -quinone however, raises questions regarding its role in the haemotoxicity associated with PQ, and/or the gametocytocidal activity of PQ [ 10 ]. A recent report has suggested the role of CYP mediated pathway in gametocytocidal activity but not with treatment safety [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative pharmacokinetics and tissue distribution of primaquine enantiomers in mice

Fasinu

Chaurasiya

Nanayakkara

et al. 2022

Malar J

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Background Primaquine (PQ) has been used for the radical cure of relapsing Plasmodium vivax malaria for more than 60 years. PQ is also recommended for prophylaxis and prevention of transmission of Plasmodium falciparum. However, clinical utility of PQ has been limited due to toxicity in individuals with genetic deficiencies in glucose 6-phosphate dehydrogenase (G6PD). PQ is currently approved for clinical use as a racemic mixture. Recent studies in animals as well as humans have established differential pharmacological and toxicological properties of the two enantiomers of PQ. This has been attributed to differential metabolism and pharmacokinetics of individual PQ enantiomers. The aim of the current study is to evaluate the comparative pharmacokinetics (PK), tissue distribution and metabolic profiles of the individual enantiomers in mice. Methods Two groups of 21 male Albino ND4 Swiss mice were dosed orally with 45 mg/kg of S-(+)-PQ and R-(−)PQ respectively. Each of the enantiomers was comprised of a 50:50 mixture of 12C- and 13C- stable isotope labelled species (at 6 carbons on the benzene ring of the quinoline core). Three mice were euthanized from each group at different time points (at 0, 0.5, 1, 2, 4, 8, 24 h) and blood was collected by terminal cardiac bleed. Liver, spleen, lungs, kidneys and brain were removed, extracted and analysed using UPLC/MS. The metabolites were profiled by tandem mass (MS/MS) fragmentation profile and fragments with 12C–13C twin peaks. Non-compartmental analysis was performed using the Phoenix WinNonLin PK software module. Results The plasma AUC0-last (µg h/mL) (1.6 vs. 0.6), T1/2 (h) (1.9 vs. 0.45), and Tmax (h) (1 vs. 0.5) were greater for SPQ as compared to RPQ. Generally, the concentration of SPQ was higher in all tissues. At Tmax, (0.5–1 h in all tissues), the level of SPQ was 3 times that of RPQ in the liver. Measured Cmax of SPQ and RPQ in the liver were about 100 and 40 times the Cmax values in plasma, respectively. Similar observations were recorded in other tissues where the concentration of SPQ was higher compared to RPQ (2× in the spleen, 6× in the kidneys, and 49× in the lungs) than in the plasma. CPQ, the major metabolite, was preferentially generated from RPQ, with higher levels in all tissues (> 10× in the liver, and 3.5× in the plasma) than from SPQ. The PQ-o-quinone was preferentially formed from the SPQ (> 4× compared to RPQ), with higher concentrations in the liver. Conclusion These studies show that in mice, PQ enantiomers are differentially biodistributed and metabolized, which may contribute to differential pharmacologic and toxicity profiles of PQ enantiomers. The findings on higher levels of PQ-o-quinone in liver and RBCs compared to plasma and preferential generation of this metabolite from SPQ are consistent with the higher anti-malarial efficacy of SPQ observed in the mouse causal prophylaxis test, and higher haemolytic toxicity in the humanized mouse model of G6PD deficiency. Potential relevance of these findings to clinical use of racemic PQ and other 8-aminoquinolines vis-à-vis need for further clinical evaluation of individual enantiomers are discussed.

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CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

Cited by 13 publications

References 35 publications

Mechanistic Modeling of Primaquine Pharmacokinetics, Gametocytocidal Activity, and Mosquito Infectivity

Mechanistic Modeling of Primaquine Pharmacokinetics, Gametocytocidal Activity, and Mosquito Infectivity

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

Comparative pharmacokinetics and tissue distribution of primaquine enantiomers in mice

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