Anti-malarial

When administered at the 3 mg/kg ED100 values established in WT mice, tafenoquine does not show any anti-malarial activity in CYP 2D knock-out mice. In humanized/CYP 2D6 knock-in mice, tafenoquine's anti-malarial activity is partially restored when tested at twice its ED100 (6 mg/kg)[1].

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Efficacy in Wild-Type (WT) Mice: In C57BL/6 (WT) mice infected with luciferase-expressing Plasmodium berghei sporozoites, oral administration of Tafenoquine at its previously established 100% efficacious dose (ED100) of 3 mg/kg (given on days -1, 0, and +1 relative to infection) completely prevented infection. No luminescence signal (indicating parasite burden) was detected at 48 or 72 hours post-infection in any of the five treated mice, and no blood-stage parasites were detected up to 31 days post-inoculation (5/5 cured). [1]
- Loss of Efficacy in CYP 2D Knock-Out (KO) Mice: When Tafenoquine was administered at the same ED100 (3 mg/kg) to CYP 2D knock-out mice (lacking the entire mouse CYP 2D gene cluster), it exhibited no anti-malarial activity. All five treated mice showed robust luminescence signals at 48 and 72 hours, comparable to untreated infected controls, and developed blood-stage infections requiring early euthanasia (0/5 cured). This demonstrates that the presence of functional CYP 2D enzymes is essential for the anti-malarial activity of Tafenoquine. [1]
- Partial Restoration of Efficacy in Humanized CYP 2D6 Knock-In (KI) Mice: In humanized mice (where the mouse CYP 2D cluster is replaced with the human CYP2D6 gene), administration of Tafenoquine at its ED100 (3 mg/kg) failed to prevent infection in all five mice (0/5 cured). However, when the dose was doubled to 6 mg/kg (2 x ED100) in this mouse model, anti-malarial activity was partially restored. At this higher dose, four out of five mice were cured (no detectable parasites at 31 days), while one mouse did not show protection at the 72-hour imaging time point but was ultimately cured by day 31. This indicates that human CYP 2D6 can mediate the activation of Tafenoquine, but with lower efficiency compared to mouse CYP 2D enzymes at the standard ED100 dose. [1]

Mouse Models and Infection: Eight- to twelve-week-old male C57BL/6 wild-type (WT), CYP 2D knock-out (KO), and humanized CYP 2D6 knock-in (KI) mice were used. Mice were intravenously inoculated in the tail vein with approximately 10,000 luciferase-expressing Plasmodium berghei sporozoites on day 0. Sporozoite viability was confirmed to be 90-100% before inoculation. [1]
- Drug Formulation and Administration: Tafenoquine was prepared as an oral suspension. The drug powder was homogenized in a vehicle consisting of 0.5% (w/v) hydroxyethyl cellulose and 0.2% (v/v) Tween-80 in distilled water. Homogenization was performed using a homogenizer with a generator at 20,000–22,000 rpm for 5 minutes in an ice bath. [1]
- Dosing Regimen: The drug suspension was administered via oral gavage using an intragastric feeder. A prophylactic regimen was employed: mice received the drug once daily for three consecutive days, on the day before infection (day -1), the day of infection (day 0), and the day after infection (day +1). Doses were based on the established ED100 (3 mg/kg) or twice the ED100 (6 mg/kg). [1]
- Efficacy Monitoring: Parasite burden was monitored non-invasively using an in vivo imaging system (IVIS). At 24, 48, and 72 hours post-infection, mice were injected intraperitoneally with D-luciferin (200 mg/kg), anesthetized with isoflurane, and imaged for bioluminescence (5-minute exposure). Blood-stage infection was also monitored by flow cytometry up to 31 days post-inoculation to determine cure rates (no detectable parasitemia). [1]

Plasma half-life: Tafenoxane has a relatively long plasma half-life of about 15 days, while primaquine has a half-life of about 6 hours. This longer half-life allows it to be administered once weekly for prophylaxis. [2] Drug interactions (pharmacokinetics): Concomitant use of tafenoxane with dihydroartemisinin-piperaquine increases the peak plasma concentration (Cmax) of tafenoxane by 38%, the area under the concentration-time curve (AUC) by 12%, and the plasma half-life by 29%. Concomitant use with chloroquine or artemether-benzylfluorene does not significantly alter the pharmacokinetics of tafenoxane. Tafenoxane does not appear to affect the pharmacokinetics of these concomitant drugs. [2]
- Metabolism (CYP2D6 dependence is inconclusive): While there is evidence that the efficacy of primaquine depends on CYP2D6 metabolism, and rodent studies suggest that tafenoxane may have similar metabolic requirements, evidence from human studies is inconclusive. A randomized, multicenter trial found no association between CYP2D6 genotype and the efficacy of tafenoxane (unlike the primaquine control group). It is currently unclear whether tafenoxane requires CYP2D6 metabolism to be active in humans. [2]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of tafenoxane during lactation. Tafenoxane can cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. If a mother needs to use tafenoxane, both the mother and infant must be tested for G6PD deficiency before administration. ◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Hemolytic anemia in G6PD deficiency: Tafenoxane, like other 8-aminoquinoline drugs, can cause hemolytic toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In a trial in heterozygous women with G6PD deficiency (Asian Mahilon variant, G6PD activity of 40-60% of normal), a single dose of 300 mg tafenoxane resulted in a decrease of approximately 23% (lowest value) in hemoglobin, slightly higher than the approximately 16% decrease observed with 15 mg primaquine daily for 14 days. Safe use requires exclusion of G6PD deficiency (patients with G6PD activity below 70% of normal should not take this drug), but heterozygous women with activity above 70% may be excluded. [2] - Ocular adverse reactions: Clinical trials have observed a high incidence (93%) of mild reversible vortex keratopathy and retinal abnormalities in subjects, with an incidence of 39%. Follow-up studies reported no related functional visual impairment. [2] - Psychiatric effects: The FDA label includes a warning that serious psychotic adverse reactions may occur in patients with a history of psychosis at the specified dose (for cure) or higher doses (for prophylaxis). [2] - Other adverse reactions: A comprehensive safety analysis reported a higher incidence (≥1%) of diarrhea, nausea, vomiting, sinusitis, gastroenteritis, and back/neck pain compared to placebo, with back/neck pain occurring in more than 5% of cases. Warnings also include methemoglobinemia and hypersensitivity reactions (e.g., angioedema). [2] - Testing requirements: Quantitative testing for G6PD deficiency is required for safe use to exclude patients with enzyme activity below 70% of normal, as qualitative screening tests may miss women with intermediate enzyme activity (30-70% of normal). [2]

[1]. Malar J. 2014 Jan 3;13:2.

[2]. J Travel Med.2018 Jan 1;25(1).

[3]. J Travel Med.2018 Dec 11.

Tafenoquine succinate is the succinate form of tafenoquine, a highly bioavailable 8-aminoquinoline derivative with antimalarial activity. While its mechanism of action is not fully elucidated, after administration, tafenoquine inhibits heme polymerase in the hematogenous phase of Plasmodium. This inhibits the conversion of toxic heme to non-toxic heme, leading to the accumulation of toxic heme within the parasite. Tafenoquine is effective against all developmental stages of Plasmodium, including the pre-erythrocytic hepatic stage. This prevents the development of the parasite's intraerythrocytic stage, which is responsible for relapses of Plasmodium vivax malaria.
See also: Tafenoquine (with active ingredient).

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Mechanism of action: Similar to primaquine, the antimalarial activity of tafenoquine requires metabolic activation by the cytochrome P450 2D (CYP 2D) enzyme. This study provides direct preclinical evidence that tafenoxane is inactive in the absence of CYP 2D metabolism (e.g., in CYP 2D knockout mice). The generated active metabolites may be the source of its activity, which may be related to redox cycles and the generation of reactive oxygen species. [1] - Pharmacogenomic significance: Due to the high polymorphism of human CYP 2D6, differences in enzyme activity (e.g., in individuals with weak or moderate metabolic capacity) may lead to treatment failure or reduced prophylactic efficacy of tafenoxane. This constitutes an important pharmacogenomics consideration when it is used. In humanized CYP 2D6 KI mice, partial recovery of efficacy was observed after doubling the dose, suggesting that dose adjustment may be necessary for individuals with reduced CYP 2D6 activity. [1] - Background of reported “resistance”: The necessity of CYP 2D6 activation provides a possible explanation for some previously reported failures of primaquine treatment, which may have been wrongly attributed to parasite resistance. Similar pharmacogenomics factors may also affect the efficacy of tafenoxane. [1] - Compounds studied: This study examined tafenoxane and another 8-aminoquinoline compound, NPC-1161B, both of which have a 5-O-aryl substituent. The activity of both compounds showed dependence on CYP 2D metabolism. [1]

C28H34F3N3O7

581.590

581.235

C, 57.83; H, 5.89; F, 9.80; N, 7.23; O, 19.26

106635-81-8

Tafenoquine;106635-80-7

163761

Solid powder

1.237g/cm3

565.6ºC at 760mmHg

295.9ºC

6.619

4

13

12

41

690

0

O=C(O)CCC(O)=O.CC(NC1=C2N=C(OC)C=C(C)C2=C(OC3=CC=CC(C(F)(F)F)=C3)C(OC)=C1)CCCN

CQBKFGJRAOXYIP-UHFFFAOYSA-N

InChI=1S/C24H28F3N3O3.C4H6O4/c1-14-11-20(32-4)30-22-18(29-15(2)7-6-10-28)13-19(31-3)23(21(14)22)33-17-9-5-8-16(12-17)24(25,26)27;5-3(6)1-2-4(7)8/h5,8-9,11-13,15,29H,6-7,10,28H2,1-4H3;1-2H2,(H,5,6)(H,7,8)

N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)quinolin-8-yl)pentane-1,4-diamine succinate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~125 mg/mL (~214.93 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (3.58 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)