Identification

Name
Tafenoquine
Accession Number
DB06608
Type
Small Molecule
Groups
Approved, Investigational
Description

Tafenoquine is an 8-aminoquinoline analogue of primaquine which varies only on the presence of a 5-phenoxy group.[1, 3] 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.[3] Tafenoquine was further developed collaboratively between GlaxoSmithKline and Medicines for Malaria Venture.[2] It was FDA approved on July 20, 2018.[6]

Structure
Thumb
Synonyms
Not Available
External IDs
SB 252263 / SB-252263-AAB
Product Ingredients
IngredientUNIICASInChI Key
Tafenoquine succinateDL5J0B8VSS106635-81-8CQBKFGJRAOXYIP-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ArakodaTablet, film coated100 mg/1Oral60 Degrees Pharmaceuticals, LLC2018-08-20Not applicableUs
Categories
UNII
262P8GS9L9
CAS number
106635-80-7
Weight
Average: 463.501
Monoisotopic: 463.208276263
Chemical Formula
C24H28F3N3O3
InChI Key
LBHLFPGPEGDCJG-UHFFFAOYSA-N
InChI
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
IUPAC Name
N4-{2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl}pentane-1,4-diamine
SMILES
COC1=CC(C)=C2C(OC3=CC=CC(=C3)C(F)(F)F)=C(OC)C=C(NC(C)CCCN)C2=N1

Pharmacology

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.[1]

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.[1]

Associated Conditions
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.[2]

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.[2]

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.[1] 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.[2]

On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites.[2]

Absorption

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.[2]

Volume of distribution

Tafenoquine presents a high volume of distribution of approximately 2 560 L.[2]

Protein binding

The plasma protein binding of tafenoquine in humans is very high and it represents about 99.5%.[5]

Metabolism

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.[2] 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.[5]

Route of elimination

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.[5]

Half life

Tafenoquine presents a long half-life of approximately 14 days.[4]

Clearance

Tafenoquine presents a low clearance of approximately 6 L/h.[2]

Toxicity

Tafenoquine can cause hemolysis in people with glucose-6-phosphate dehydrogenase deficiency.[1] In preclinical studies, renal cell adenomas and carcinomas are increased in male rats with an overdose administration. However, this drug does not seem to be carcinogenic in humans and it was shown to lack mutagenic potential. In fertility studies, tafenoquine resulted in a reduced number of viable fetuses, implantation sites and corpora lutea.[Label]

Affected organisms
  • Plasmodium
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineThe metabolism of Tafenoquine can be decreased when combined with 4-Methoxyamphetamine.
AbemaciclibThe excretion of Abemaciclib can be decreased when combined with Tafenoquine.
AbirateroneThe metabolism of Tafenoquine can be decreased when combined with Abiraterone.
AcebutololThe metabolism of Tafenoquine can be decreased when combined with Acebutolol.
AcepromazineThe risk or severity of QTc prolongation can be increased when Tafenoquine is combined with Acepromazine.
AceprometazineThe risk or severity of QTc prolongation can be increased when Tafenoquine is combined with Aceprometazine.
AcetaminophenThe metabolism of Tafenoquine can be decreased when combined with Acetaminophen.
AcetophenazineThe risk or severity of QTc prolongation can be increased when Tafenoquine is combined with Acetophenazine.
AcetyldigitoxinThe serum concentration of Acetyldigitoxin can be increased when it is combined with Tafenoquine.
AcetyldigoxinThe serum concentration of Acetyldigoxin can be increased when it is combined with Tafenoquine.
Food Interactions
Not Available

References

General References
  1. Rajapakse S, Rodrigo C, Fernando SD: Tafenoquine for preventing relapse in people with Plasmodium vivax malaria. Cochrane Database Syst Rev. 2015 Apr 29;(4):CD010458. doi: 10.1002/14651858.CD010458.pub2. [PubMed:25921416]
  2. Ebstie YA, Abay SM, Tadesse WT, Ejigu DA: Tafenoquine and its potential in the treatment and relapse prevention of Plasmodium vivax malaria: the evidence to date. Drug Des Devel Ther. 2016 Jul 26;10:2387-99. doi: 10.2147/DDDT.S61443. eCollection 2016. [PubMed:27528800]
  3. Peters W: The evolution of tafenoquine--antimalarial for a new millennium? J R Soc Med. 1999 Jul;92(7):345-52. [PubMed:10615272]
  4. Melariri P, Kalombo L, Nkuna P, Dube A, Hayeshi R, Ogutu B, Gibhard L, deKock C, Smith P, Wiesner L, Swai H: Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice. Int J Nanomedicine. 2015 Feb 20;10:1493-503. doi: 10.2147/IJN.S76317. eCollection 2015. [PubMed:25759576]
  5. Grayson L., Cosgrove S., Crowe S., Hope W., McCarthy J., Mills J., Mouton J., Paterson D. (2017). Kucer's the use of antibiotics (7th ed.). CRC Press LLc.
  6. FDA approval [Link]
External Links
ChemSpider
103196
ChEBI
141487
ChEMBL
CHEMBL298470
PharmGKB
PA166115580
Wikipedia
Tafenoquine
FDA label
Download (369 KB)
MSDS
Download (182 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedBasic SciencePlasmodium Infections1
1CompletedOtherMalaria caused by plasmodium vivax1
1CompletedTreatmentMalaria caused by plasmodium vivax2
2CompletedTreatmentFalciparum Parasitaemia1
2CompletedTreatmentMalaria caused by plasmodium vivax1
2CompletedTreatmentPlasmodium Infections2
2RecruitingPreventionHealthy Volunteers1
2RecruitingTreatmentMalaria caused by plasmodium vivax1
2TerminatedTreatmentPlasmodium Infections / Plasmodium Vivax1
3CompletedTreatmentMalaria caused by plasmodium vivax1
3RecruitingTreatmentMalaria caused by plasmodium vivax1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolubleMelariri P. et al. (2015). Int J Nanomedicine; 10: 1493-1503
logS2.04Marella A. et al. (2013). Saudi Pharm J. Jan; 21 (1): 1-12
pKa9.5Marella A. et al. (2013). Saudi Pharm J. Jan; 21 (1): 1-12
Predicted Properties
PropertyValueSource
Water Solubility0.00137 mg/mLALOGPS
logP5.07ALOGPS
logP4.97ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)17.14ChemAxon
pKa (Strongest Basic)10.2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area78.63 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity122.55 m3·mol-1ChemAxon
Polarizability47.38 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Ebstie YA, Abay SM, Tadesse WT, Ejigu DA: Tafenoquine and its potential in the treatment and relapse prevention of Plasmodium vivax malaria: the evidence to date. Drug Des Devel Ther. 2016 Jul 26;10:2387-99. doi: 10.2147/DDDT.S61443. eCollection 2016. [PubMed:27528800]
Kind
Protein
Organism
Plasmodium falciparum (isolate 3D7)
Pharmacological action
Yes
Actions
Substrate
General Function
Not Available
Specific Function
Electron transfer activity
Gene Name
Not Available
Uniprot ID
C6KT68
Uniprot Name
Ferredoxin--NADP reductase, apicoplast
Molecular Weight
43778.59 Da
References
  1. Ebstie YA, Abay SM, Tadesse WT, Ejigu DA: Tafenoquine and its potential in the treatment and relapse prevention of Plasmodium vivax malaria: the evidence to date. Drug Des Devel Ther. 2016 Jul 26;10:2387-99. doi: 10.2147/DDDT.S61443. eCollection 2016. [PubMed:27528800]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. Clinical trials [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. Tafenoquine FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
The FDA label recommends to avoid the co-administration of tafenoquine with MATE substrate drugs.
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. Tafenoquine FDA label [File]

Drug created on March 19, 2008 10:40 / Updated on November 02, 2018 09:16