Review on Arakoda (Tafenoquine) and its approach as an Anti-Malarial Agent.

 

Syeda Sana1, Mohsina Abed2

1Deccan School of Pharmacy, Hyderabad.

2Assistant Professor, Deccan School of Pharmacy, Hyderabad.

*Corresponding Author E-mail: syedasanadsop@gmail.com

 

ABSTRACT:

Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. Antimalarial agents are drugs used for the treatment or prophylaxis of malaria. Malaria is caused by four species of Plasmodium, such as Plasmodium falciparum, P. malariae, P. ovale, and P. vivax. Arakoda contains tafenoquine succinate, an antimalarial agent for oral administration. The molecular formula of tafenoquine succinate is C24H28F3N3O3∙C4H6O4 and its molecular weight is 581.6 as the succinate salt. It is given in prophylaxis of malaria patient aged 18 years older. Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species. G6PD test is performed before giving the drug. Analytical studies were on NMR, IR, MS, HPLC, Flourimetry analysis. In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436mcg against blood stages of seven strains of P. falciparum. The long‐acting 8‐aminoquinoline tafenoquine (TQ) co-administered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration   therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Volume of distribution. The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. Routes of elimination are through feces.

 

KEYWORDS: TQ, PQ, Plasmodium vivax, P. falciparum, tafenoquine, G6PD, Arakoda, 5,6 ortho-qunine, CYP 2D6, Mefloquine.

 

 


INTRODUCTION:

Tafenoquine (TQ) is an 8-aminoquinoline derivative that had just received approval by the US Food and Drug Administration (FDA, July 2018) and the Australian Therapeutic Goods Administration (TGA, September 2018) for a radical cure of Plasmodium vivax malaria (US/Australia brand name Krintafel/Kozenis, developed by GlaxoSmithKline [GSK, London, UK]) together with Medicines for Malaria Venture (MMV, Geneva, Switzerland) and for prophylaxis of malaria (US/Australia brand name Arakoda/Kodatef, developed by 60 Degrees Pharmaceuticals (Washington DC, USA) together with the US Army)1..

 

TQ passed more than four decades of development as an antimalarial drug and was initially under investigation as a prophylactic antimalarial agent for preventing Plasmodium falciparum malaria but without final submission of the dossier for market authorization1-5.

 

 

Fig 1. Life Cycle of Plasmodium Vivax5

Arakoda contains tafenoquine succinate, an antimalarial agent for oral administration. The structural formula of tafenoquine succinate is a synthetic analogue of primaquine5.tafenoquine is an 8-aminoquinoline antimalarial drug indicated for the prophylaxis of malaria in patients aged 18 years and older5.

 

Fig 2 Structure of ARAKODA

 


Synthesis:

 

Fig 3 Synthesis of Arakoda

 


 

Chlorination of 6-methoxy-4-methylquinolin-2(1H)-one (I) with SO2Cl2 in hot acetic acid gives the 5-chloro derivative (II), which is nitrated with HNO3 in H2SO4 to yield the 8-nitroquinolinone (III). Condensation of compound (III) with 3-(trifluoromethyl) phenol (IV) by means of KOH in NMP provides the diaryl ether (V), which is treated with refluxing POCl3 to afford the 2-chloroquinoline (VI)1. Reaction of compound (VI) with MeONa in refluxing methanol results in the 2,6-dimethoxyquinoline derivative (VII), which is reduced with hydrazine over Pd/C to give the 8-aminoquinoline derivative (VIII). Condensation of aminoquinoline (VIII) with N-(4-iodopentyl) phthalimide (IX) by means of diisopropylamine in hot NMP yields the phthalimido precursor (X), which is finally cleaved with hydrazine in refluxing ethanol gives tafenoquine2.

 

MATERIALS AND METHODS:

MTD rat study:

With the goal of identifying the maximum tolerated dose, groups of 5 male and 5 female Sprague Dawley (SD) rats were administered a single oral dose of 0 (vehicle), 125, 250, 400 or 700mg/kg tafenoquine succinate (dose expressed as free base) in 1%/0.4% methylcellulose/Tween 80 in water, at a dose volume of 10mL/kg [Note the 400mg/kg dose group was administered an actual dose of 506mg/kg due to a higher concentration dose formulation being prepared whereas all other groups were within 12% of nominal dose3.

 

The day of dosing was designated Day 1. Animals were observed for 7 days following dosing. Animal viability checks and physical observations were made daily, body weights were recorded pre-dose and twice during the study, and clinical pathology parameters were assessed on Day 7. Following Day 7 assessments animals were euthanized without further examination, although any animals dying earlier than the scheduled end of study were grossly examined at necropsy. The dose formulation for each group was analyzed to confirm the absence (control) or actual concentration of tafenoquine.

 

ANTIMICROBIAL ACTIVITY:

Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species that include P. falciparum and P. vivax. The activity of tafenoquine against the pre-erythrocytic liver stages of the parasite, prevents the development of the erythrocytic forms of the parasite. Method of agar dilution was performed to study the antimicrobial activity as formerly described2. All compounds were dissolved in dimethyl sulfoxide (DMSO) and were separately mixed with 1mL of Mueller Hinton (MH) broth. Then, the final concentrations of 32-256µg/mL were carried out by transferring the mixture to the MH agar, and the negative control was MH broth. The cell concentration of microbes used in this study was adjusted to 108 cells/mL in 0.9% normal saline after the microbes were cultured at 37°C for 24 h in the MH broth. The inhibitions of microbial growth were detected in each compound following the inoculation onto the MH agar, and incubation at 37°C for 24 h.

 

CLINICAL STUDIES:

Clinical Trials 1, 2, and 3 Three double-blind, randomized, controlled studies have been performed to evaluate the efficacy of ARAKODA. Trial 1 (NCT #02491606) was a Phase IIb, placebo-controlled study conducted in Kenya, an area of holoendemic P. falciparum malaria. After taking a three-day presumptive course of halofantrine to eliminate any existing parasitemia, subjects were randomized into one of four groups (placebo and three different ARAKODA dosing groups; one group received 200mg once daily for 3 days, then a maintenance regimen of weekly dose of 200mg for 10-15 weeks). Sixty-one percent of subjects were male. The mean age was 32.4 years (range 17-55). Subjects were evaluated for parasitemia by weekly blood smears. Protective efficacy at 15 weeks was defined based on the reduced incidence of parasitemia during the prophylaxis phase relative to placebo. The results in the intention-to-treat population, which included all subjects who received three doses of halofantrine and were randomized, are shown in Table below:

 

Table 1 Placebo of Arakoda

Criteria

Placebo

Arakoda

Number of subjects

94

93

Subjects free of parasitemia

6(6.4%)

68(73.1%)

Subject with parasitemia

86(91.5%)

12(12.9%)

Subjects with missing data

2(2.1%)

13(14.0%)

Protective efficacy[98.75%Cl]2

-

71.3%

 

·       The Trial 3 compared Arakoda with mefloquine for the prophylaxis of both P. falciparum and P. vivax malaria in healthy non-immune soldiers deployed to East Timor (now Timor-Leste). No subject developed malaria during the 26-week prophylactic phase.

·       Subjects were exposed to P. vivax and there is a high likelihood that the study subjects were also exposed to P. falciparum. Since the precise degree of exposure to malaria in study subjects is unknown, this study provides only supportive evidence of efficacy.

 

Clinical Trial 7

·       In a randomized, double-blind, placebo-controlled trial (Trial 7) in healthy, non-immune volunteers, ARAKODA was shown to have prophylactic activity directed against blood-stage P. falciparum parasites. Twelve subjects received ARAKODA (200mg once daily for 3 days, then 200mg on 10 day) and 4 subjects received placebo.

·       On Day 13, subjects were inoculated with erythrocytes containing viable P. falciparum parasites. Fifteen subjects (93.8%) were of white race. The mean age was 27.5 years (range 20-42). The mean body weight was 72.3kg (range 56- 97.7).

·       The efficacy endpoint was parasitemia by Day 34; parasitemia was based on detection of P. falciparum 18S ribosomal DNA by real time polymerase chain reaction assay (PCR). There was a statistically significant difference in malaria incidence between the two groups; 4/4 (100%) subjects in the placebo group had detectable parasites from Day 17 compared to 0/12 (0%) subjects on ARAKODA were PCR negative at all visits.

 

ADVERSE REACTIONS:

CLINICAL TRIALS EXPERIENCE5:

In total, 3 clinical studies with TQ as an anti-malarial agent have been conducted until October 2018. Results of the first TQ clinical trial in humans were published in 1998, showing that TQ was safe and well tolerated.14 The molecule’s promising half-life of 15 days initiated a series of clinical studies that led to established and consolidated safety, tolerability, and efficacy data.

 

The safety of tafenoquine was studied in clinical trials at various doses and regimens in 3,184 subjects. The recommended ARAKODA regimen was evaluated in 825 subjects in 5 controlled clinical trials (Trials 1, Trial 2, Trial 3, Trial 4 and Trial 5).

 

The mean duration of exposure to ARAKODA in these five clinical trials was 21 weeks (range 10-29 weeks). Trial 1, 2 and 4 were conducted in healthy semi-immune volunteers in Ghana or Kenya and were placebo-controlled; a mefloquine arm was included in Trials 2 and 4 as a benchmark. Trial 3, an active comparator (mefloquine) controlled trial was conducted in healthy soldiers deployed in East Timor (Timor Leste)5.

 

A placebo-controlled Trial 5 was conducted in healthy volunteers in the United States and United Kingdom. The mean age of the subjects included in the five trials was 29 years (range 17 to 69 years); 84% were male.

 

 


Table 2 Adverse Reactions Reported with ARAKODA in Trial 3 and Pooled Trials 1, 2, 4, and 5 Adverse reactions occurring in ≥1% of subjects in the ARAKODA group in the placebo controlled pooled Trials 1, 2, 3, and 4 are presented5

ADVERSE REACTION

ARAKODA (TAFENOQUNINE)

PLACEBO n=295

MEFLOQUINE n=145

Nervous system disorders

35

34

47

·    Headache

32

32

44

·    Dizziness

5

3

10

Musculoskeletal and connective disorder

27

26

37

·    back pain

14

9

11

Gastrointestinal disorder

31

33

46

·    Diarrhoea

5

3

1

·    Nausea

·    Vomiting

5

2

2

2

2

1

Investigations

8

7

11

·    Alanine Amino Transferase(AAT) increased/abnormal

4

2

3

·    Psychiatric Disorder

2

1

2

·    Any sleep symptoms 

1

1

0

·    Depression

1

0

0

·    Insomnia

1

1

0

 


Trials 2 and 4 included mefloquine arm in addition to placebo

·       Arakoda was administered as 200mg daily for 3 days, then 200mg weekly

·       Mefloquine was administered as 250mg daily for 3 days, then 250mg weekly 

·       Headache Includes headache, sinus headache, migraine and tension headache.

·       Includes dizziness and dizziness postural Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism.

 

Adverse Reactions Reported In < 1% of Subjects Receiving ARAKODA In Trials 1 To 5

·       The following selected adverse reactions were reported in subjects receiving Arakoda (tafenoquine) in Trials 1 to 5 at a rate of less than 1%.

·       Blood and lymphatic system disorders: hemolytic anemia, anemia, thrombocytopenia

·       Ear and labyrinth disorders: hyperacusis, Meniere’s disease

·       Eye disorders: night blindness, photophobia, blurred vision, visual acuity reduced, visual impairment, vitreous floaters

·       Hepatobiliary disorders: hyperbilirubinemia, jaundice cholestatic3.

·       Immune system disorders: hypersensitivity

·       Investigations: blood bilirubin increased, blood creatinine increased, glomerular filtration rate decreased

·       Nervous system disorders: amnesia, coordination abnormal, hyperesthesia, hypoesthesia, somnolence, syncope, tremor, visual field defect3,5

·       Psychiatric disorders: agitation, neurosis

·       Skin and subcutaneous tissue disorders: urticaria.

 

USES:

·       It is extensively used for the radical cure of relapsing vivax malaria1,5.

·       It invariably kills gametocytes of all the species or inhibits their growth and development in the mosquito.

 

SPECTRAL ANALYSIS:

H1 NMR1,3

 

Fig 4H1 NMR Spectral Analysis of Arakoda

IR SPECTRUM4:

 

Fig 5 IR Spectral Analysis of Arakoda

 

MASS SPECTROSCOPY[MS]2:

 

Fig 6 Mass Spectrum of Arakoda

 

 

High Performance Liquid chromatography:

Method was developed for the determination of tafenoquine (I) in human plasma using high-performance liquid chromatography–tandem mass spectrometry. Prior to analysis, the protein in plasma samples was precipitated with methanol containing [2H315N] tafenoquine (II) to act as an internal standard. The supernatant was injected onto a Genesis-C18 column without any further clean-up3. The mass spectrometer was operated in the positive ion mode, employing a heat assisted nebulisation, electrospray interface. Ions were detected in multiple reaction monitoring mode. The assay required 50μl of plasma and was precise and accurate within the range 2 to 500ng/ml. The average within-run and between-run relative standard deviations were <7% at 2ng/ml and greater concentrations. The average accuracy of validation standards was generally within ±4% of the nominal concentration.

 

There was no evidence of instability of I in human plasma following three complete freeze–thaw cycles and samples can safely be stored for at least 8 months at approximately −70°C. The method was very robust and has been successfully applied to the analysis of clinical samples from patients and healthy volunteers dosed with I9.

 


 

Fig 7 HPLC Method Development Of Arakoda

 


 

REFERENCE:

1.     Peters W (1999). "The evolution of tafenoquine--antimalarial for a new millennium?". J R Soc Med. 92 (7): 345–52. doi:10.1177/014107689909200705. PMC 1297286. PMID

2.     Haston JC, Hwang J, Tan KR (November 2019). "Guidance for Using Tafenoquine for Prevention and Antirelapse Therapy for Malaria — United States, 2019"(PDF). MMWR. Morbidity and Mortality Weekly Report. 68 (46): 1062–1068. doi:10.15585/mmwr.mm6846a4. PMID

3.     "Tafenoquine Succinate (Krintafel) Monograph for Professionals". Drugs.com. Retrieved 22 November 2019.

4.     Hounkpatin, Aurore B; Kreidenweiss, Andrea; Held, Jana (March 2019). "Clinical utility of tafenoquine in the prevention of relapse of Plasmodium vivax malaria: a review on the mode of action and emerging trial data". Infection and Drug Resistance. Volume 12: 553–570. doi:10.2147/IDR.S151031.

5.     "Krintafel Prices, Coupons and Patient Assistance Programs". Drugs.com. Retrieved 22 November 2019.

6.     "Tafenoquine Approved for Malaria Prophylaxis and Treatment". Centers for Disease Control and Prevention (CDC). 25 April 2019. Retrieved 22 November 2019.

 

 

 

Received on 30.03.2020            Modified on 29.05.2020

Accepted on 21.07.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):2336-2340.

DOI: 10.52711/0974-360X.2021.00412