Anti-malarial

When tafenoquine is administered at the 3 mg/kg ED100 values that were established in WT mice, it shows no anti-malarial activity in CYP 2D knock-out mice. When tested at twice its ED100 (6 mg/kg), tafenoquine's anti-malarial activity is partially restored in humanized/CYP 2D6 knock-in mice[1].

Absorption, Distribution and Excretion
The first-in-human pharmacokinetic study showed a tmax of 13.8 hours and this study suggested that the prolonged absorption from the gut can be due to absorption in the distal gastrointestinal tract combined with a slow clearance. The AUC and Cmax demonstrated an intersubject variability. The bioavailability of tafenoquine is increased in the presence of a high-fat meal by modifying the amount of drug absorbed rather than the rate of absorption. Once absorbed, the concentration of tafenoquine in the whole body is two-fold higher than the corresponding concentration in plasma and it seems to be highly distributed in the liver showing an AUC of approximately 80 times more than what is found in the plasma.
After degradation by different metabolic pathways, tafenoquine is slowly excreted from the body primarily in the feces and renal elimination of the unchanged form is very low.
Tafenoquine presents a high volume of distribution of approximately 2 560 L.
Tafenoquine presents a low clearance of approximately 6 L/h.

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Metabolism / Metabolites
The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. This activation step produces the metabolite 5,6 ortho quinone tafenoquine. This metabolite is internalized by the parasite and reduced to radicals by ferredoxin-NADP+ reductase and diflavin reductase enzymes. In the human, tafenoquine is metabolized by several metabolic pathways including O-demethylation, N-dealkylation, N-oxidation and oxidative deamination as well as C-hydroxylation of the 8-aminoalkylamino side chain.

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Biological Half-Life
Tafenoquine presents a long half-life of approximately 14 days.

Hepatotoxicity
In prelicensure clinical trials, tafenoquine was linked to a low rate of transient and mild serum aminotransferase elevations during therapy, but not to serum enzyme elevations with jaundice or with clinically apparent acute liver injury. It has had limited widescale use but appears to have a low risk for hepatotoxicity, and its safety profile has been similar to that of primaquine. Tafenoquine can cause hemolysis in patients with G6PD deficiency, which can result in mild indirect hyperbilirubinemia and jaundice, but without significant accompanying evidence of liver injury.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of tafenoquine during breastfeeding. Tafenoquine can cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. If tafenoquine is needed by the mother, testing the mother and infant for G6PD deficiency is required before the drug is given. Because the half-life of tafenoquine averages 15 days, the manufacturer recommends that breastfeeding should not breastfeed for 3 months after the dose if the infant is G6PD deficient.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
The plasma protein binding of tafenoquine in humans is very high and it represents about 99.5%.

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

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

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

N(4)-{2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl}pentane-1,4-diamine is an aminoquinoline that is 8-aminoquinoline which is substituted by methoxy groups at positions 2 and 6, a methyl group at position 4, and a m-(trifluoromethyl)phenoxy group at position 5, and in which the amino substituent at position 8 is itself substituted by a 5-aminopentan-2-yl group. It is a member of (trifluoromethyl)benzenes, an aminoquinoline, an aromatic ether, a primary amino compound and a secondary amino compound.
Tafenoquine is an 8-aminoquinoline analogue of primaquine which varies only on the presence of a 5-phenoxy group. It was discovered by the scientists at the Walter Reed Army Institute of Research in 1978 as a substitute for primaquine that would be more effective against relapsing vivax malaria. Tafenoquine was further developed collaboratively between GlaxoSmithKline and Medicines for Malaria Venture. It was FDA approved on July 20, 2018.
Tafenoquine is an aminoquinoline that is used in combination with other antimalarials for the prevention of relapse of Plasmodium vivax malaria and by itself as prophylaxis against all species of malaria. Tafenoquine has been linked to low rates of transient and asymptomatic serum enzyme elevations during therapy but has not been associated with instances of clinically apparent acute liver injury.
Tafenoquine is an orally bioavailable 8-aminoquinoline derivative, with antimalarial activity. Although the mechanism is not completely understood, upon administration, tafenoquine inhibits the parasitic enzyme heme polymerase in the blood stages of the parasites. This inhibits the conversion of the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite. Tafenoquine is active against all the stages of Plasmodium species and is also active against the pre-erythrocytic liver stages of the parasites. This prevents the development of the erythrocytic forms of the parasite which are responsible for relapses in P. vivax malaria.
See also: Tafenoquine Succinate (active moiety of).

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Drug Indication
Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria. Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by _Plasmodium vivax_, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses.
FDA Label

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Mechanism of Action
The mechanism of action of tafenoquine is not well established but studies have reported a longer and more effective action when compared to primaquine. The active moiety of tafenoquine, 5,6 ortho quinone tafenoquine, seems to be redox cycled by _P. falciparum_ which are upregulated in gametocytes and liver stages. Once inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl radicals. It is thought that these radicals produce leads to the parasite death. On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites.

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Pharmacodynamics
In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436 mcg against blood stages of seven strains of _P. falciparum_. In chloroquine-resistant _P. falciparum_ strains the IC50 of tafenoquine was greater when compared with primaquine and it ranged from 0.5 to 33.1 mcg. In studies evaluating the transmission-blocking activity of tafenoquine against the sporogonic stage of _P. vivax_, it was showed a reduced transmission at doses higher than 25 mg/kg. In clinical trials, it was reported a tafenoquine-induced relapse prevention of 91.9% in cases of vivax malaria when pretreated with chloroquine. In prophylactic studies, tafenoquine showed an efficacy range from 84 to 87% against falciparum malaria and 99.1% against vivax malaria.

C24H28F3N3O3

463.50

463.208

C, 62.19; H, 6.09; F, 12.30; N, 9.07; O, 10.36

106635-80-7

Tafenoquine Succinate;106635-81-8

115358

Light yellow solid powder

1.237g/cm3

565.6ºC at 760mmHg

295.9ºC

8.17E-13mmHg at 25°C

1.572

6.684

2

9

9

33

597

0

CC1=CC(OC)=NC2=C1C(OC3=CC=CC(C(F)(F)F)=C3)=C(OC)C=C2NC(CCCN)C

LBHLFPGPEGDCJG-UHFFFAOYSA-N

InChI=1S/C24H28F3N3O3/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/h5,8-9,11-13,15,29H,6-7,10,28H2,1-4H3

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

WR-238605, WR 238605, WR238605, SB-252263-AAB; SB252263-AAB; SB 252263-AAB; Tafenoquine; Krintafel

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~93 mg/mL ( ~200.65 mM ) Ethanol : ~93 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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