Four Times of Relapse of Plasmodium vivax Malaria Despite Primaquine Treatment in a Patient with Impaired Cytochrome P450 2D6 Function

Choi, Sungim; Choi, Hosoon; Park, Seong Yeon; Kwak, Yee Gyung; Song, Je Eun; Shin, So Youn; Baek, Ji Hyeon; Shin, Hyun-Il; Oh, Hong Sang; Kim, Yong Chan; Yeom, Joon‐Sup; Han, Jin‐Hee; Kim, Min Jae

doi:10.3347/kjp.2022.60.1.39

Cited by 5 publications

(3 citation statements)

References 16 publications

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“… 38 A report also confirms impaired CYP2D6 function in a patient with four relapses of P. vivax malaria despite primaquine treatment in Korea. 39 In contrast, previous studies have shown that low CYP2D6 metabolism did not appear to be associated with relapse in patients with tafenoquine use. 40 41 Therefore, this is another advantage of tafenoquine over primaquine.…”

Section: Discussionmentioning

confidence: 82%

Cost-Benefit Analysis of Tafenoquine for Radical Cure of Plasmodium vivax Malaria in Korea

Suh

Kim

Kim³

et al. 2022

J Korean Med Sci

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Background Plasmodium vivax malaria has a persistent liver stage that causes relapse, and introducing tafenoquine to suppress relapse could aid in disease eradication. Therefore, we assessed the impact of tafenoquine introduction on P. vivax malaria incidence and performed a cost-benefit analysis from the payer’s perspective. Methods We expanded the previously developed P. vivax malaria dynamic transmission model and calibrated it to weekly civilian malaria incidences in 2014–2018. Primaquine and tafenoquine scenarios were considered by assuming different relapse probabilities, and relapse and total P. vivax malaria cases were predicted over the next decade for each scenario. We then estimated the number of cases prevented by replacing primaquine with tafenoquine. The cost and benefit of introducing tafenoquine were obtained using medical expenditure from a nationwide database, and a cost-benefit analysis was conducted. A probabilistic sensitivity analysis was performed to assess the economic feasibility robustness of tafenoquine introduction under uncertainties of model parameters, costs, and benefits. Results Under 0.04 primaquine relapse probability, the introduction of tafenoquine with relapse probability of 0.01 prevented 129 (12.27%) and 35 (77.78%) total and relapse cases, respectively, over the next decade. However, under the same relapse probability as primaquine, introducing tafenoquine had no additional preventative effect. The 14-day primaquine treatment cost was $3.71. The tafenoquine and the glucose-6-phosphate dehydrogenase rapid diagnostic testing cost $57.37 and $7.76, totaling $65.13. The average medical expenditure per malaria patient was estimated at $1444.79. The cost-benefit analysis results provided an incremental benefit-cost ratio (IBCR) from 0 to 3.21 as the tafenoquine relapse probability decreased from 0.04 to 0.01. The probabilistic sensitivity analysis showed an IBCR > 1, indicating that tafenoquine is beneficial, with a probability of 69.1%. Conclusion Tafenoquine could reduce P. vivax malaria incidence and medical costs and bring greater benefits than primaquine.

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Section: Discussionmentioning

confidence: 82%

Cost-Benefit Analysis of Tafenoquine for Radical Cure of Plasmodium vivax Malaria in Korea

Suh

Kim

Kim³

et al. 2022

J Korean Med Sci

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“…Antimalarial drugs, including quinine and CQ, act on the blood forms of the malaria parasite to clear the parasite; primaquine is also used to eliminate hypnozoites in South Korea [16][17][18]. Therefore, we developed novel molecules with a CQ structural template, including a quinolone moiety and a modified side chain (e.g., α, β-unsaturated amide) such that SKM13 could be a used in a strategy to further develop antimalarial drugs [6].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice

Hong,

Moon,

Trinh

et al. 2024

Parasites Hosts Dis

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Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity of the 9 antimalarial compounds chemically synthesized using SKM13-2HCl. Except for SKM13-2HCl, the 5 newly synthesized compounds had a 50% cytotoxic concentration (CC50) > 100 µM, indicating that they would be less cytotoxic than SKM13-2HCl. Among the 5 compounds, only SAM13-2HCl outperformed SKM13-2HCl for antimalarial activity, showing a 3- and 1.3-fold greater selective index (SI) (CC50/IC50) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) Plasmodium falciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lower polarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was more toxic in the rodent model. Consequently, SAM13-2HCl containing morpholine was selected from screening a combination of pharmacologically significant structures as being the most effective in vitro against human-infectious P. falciparum but was less efficient in vivo in a P. berghei-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant P. falciparum infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.

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“…Clinical studies revealed that relapse was predominantly found in patients who were poor or intermediate metabolizers [17][18][19][20]. Multiple episodes of P. vivax relapse were reported in a patient who was an intermediate metabolizer with less than 50% CYP2D6 activity and treated with high-dose primaquine (30 mg daily for 14 days) to prevent malaria recurrence [21]. Taken together, genetic variations in CYP2D6 should be considered when administering primaquine in P. vivax patients.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 2D6 (CYP2D6) and glucose-6-phosphate dehydrogenase (G6PD) genetic variations in Thai vivax malaria patients: Implications for 8-aminoquinoline radical cure

et al. 2022

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Background Primaquine and tafenoquine are the only licensed drugs that effectively kill the hypnozoite stage and are used to prevent Plasmodium vivax malaria relapse. However, both primaquine and tafenoquine can cause acute hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient people with varying degrees of severity depending on G6PD variants. Additionally, primaquine efficacy against malaria parasites was decreased in individuals with impaired cytochrome P450 2D6 (CYP2D6) activity due to genetic polymorphisms. This study aimed to characterize G6PD and CYP2D6 genetic variations in vivax malaria patients from Yala province, a malaria-endemic area along the Thai–Malaysian border, and determine the biochemical properties of identified G6PD variants. Methodology/Principle findings Multiplexed high-resolution melting assay and DNA sequencing detected five G6PD variants, including G6PD Kaiping, G6PD Vanua Lava, G6PD Coimbra, G6PD Mahidol, and G6PD Kerala-Kalyan. Biochemical and structural characterization revealed that G6PD Coimbra markedly reduced catalytic activity and structural stability, indicating a high susceptibility to drug-induced hemolysis. While Kerala-Kalyan had minor effects, it is possible to develop mild adverse effects when receiving radical treatment. CYP2D6 genotyping was performed using long-range PCR and DNA sequencing, and the phenotypes were predicted using the combination of allelic variants. Decreased and no-function alleles were detected at frequencies of 53.4% and 14.2%, respectively. The most common alleles were CYP2D*36+*10 (25.6%), *10 (23.9%), and *1 (22.2%). Additionally, 51.1% of the intermediate metabolizers showed CYP2D6*10/*36+*10 as the predominant genotype (15.9%). Conclusions/Significance Our findings provide insights about genetic variations of G6PD and CYP2D6 in 88 vivax malaria patients from Yala, which may influence the safety and effectiveness of radical treatment. Optimization of 8-aminoquinoline administration may be required for safe and effective treatment in the studied population, which could be a significant challenge in achieving the goal of eliminating malaria.

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Four Times of Relapse of Plasmodium vivax Malaria Despite Primaquine Treatment in a Patient with Impaired Cytochrome P450 2D6 Function

Cited by 5 publications

References 16 publications

Cost-Benefit Analysis of Tafenoquine for Radical Cure of Plasmodium vivax Malaria in Korea

Cost-Benefit Analysis of Tafenoquine for Radical Cure of Plasmodium vivax Malaria in Korea

Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice

Cytochrome P450 2D6 (CYP2D6) and glucose-6-phosphate dehydrogenase (G6PD) genetic variations in Thai vivax malaria patients: Implications for 8-aminoquinoline radical cure

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