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General Description:

Tafenoquine, identified by CAS number 106635-80-7, is a notable compound with significant therapeutic applications. 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.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tafenoquine undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tafenoquine are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tafenoquine is an important consideration for its dosing schedule: Tafenoquine presents a long half-life of approximately 14 days. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tafenoquine exhibits a strong affinity for binding with plasma proteins: The plasma protein binding of tafenoquine in humans is very high and it represents about 99.5%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tafenoquine from the body primarily occurs through: 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tafenoquine is distributed throughout the body with a volume of distribution of: Tafenoquine presents a high volume of distribution of approximately 2 560 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tafenoquine is a critical factor in determining its safe and effective dosage: Tafenoquine presents a low clearance of approximately 6 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tafenoquine exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tafenoquine functions by: 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Tafenoquine is categorized under the following therapeutic classes: Aminoquinolines, Anti-Infective Agents, Antimalarials, Antiparasitic Agents, Antiparasitic Products, Insecticides and Repellents, Antiprotozoals, Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, OCT2 Inhibitors, Quinolines. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tafenoquine include:

• Water Solubility: Insoluble
• logS: 2.04
• pKa: 9.5