WWII-Era 8-aminoquinoline Neurotoxicity Screening Program
During WWII and the years that followed, having accepted the clinical evidence of neurotoxicity in several of the 8-aminoquinolines which had been widely used by allied troops, the U.S. government conducted a dedicated neurotoxicity screening program using primate models, in order to find a safe alternative treatment and prevention drug for P. vivax malaria. This program found extensive, direct physical evidence of permanent brain damage in primates administered 8-aminoquinolines, in parts of the brain linked to the chronic neuropsychiatric symptoms also exhibited by humans who are adversely affected by these drugs.
- Coming soon.
Tafenoquine Pre-clinical Studies
Summary of pre-clinical studies.
- Coming soon.
Tafenoquine Clinical Studies prior to 2010
Summary of clinical studies.
- Coming soon.
2009 Agboruche et al. Neurotoxicity Study at WRAIR
- Summary of this study and it’s significance. Coming soon.
Cytochrome P450 2D6 Mediated Metabolism of the 8-aminoquinolines
Scientists have discovered that the 8-aminoquinolines (including primaquine and tafenoquine) are largely ineffective because they need to be metabolised by an enzyme known as CYP2D6. Up to one quarter of the population carry a genetic deficiency which means they remain at risk of contracting malaria even if they are fully compliant with the prescribed drug regimen.
S. Ganesan et al., “Cytochrome P(450)-dependent toxic effects of primaquine on human erythrocytes,” Toxicology and Applied Pharmacology, vol. 241, 2009, pp. 14-22. https://doi.org/10.1016/j.taap.2009.07.012
B.S. Pybus et al., “Malaria CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine,” Malaria Journal, vol. 11, 2012, p. 259. https://doi.org/10.1186/1475-2875-12-212
J.W. Bennett et al., “Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria,” New England Journal of Medicine, vol. 369, 2013, pp. 1381-82. https://doi.org/10.1056/NEJMc1301936
G.A. Deye, A.J. Magill, “Primaquine for prophylaxis of malaria: Has the CYP sailed?,” Journal of Travel Medicine, vol. 21, 2014, pp. 67-69. https://doi.org/10.1111/jtm.12080
C. Vuong et al., “Differential cytochrome P450 2D metabolism alters tafenoquine pharmacokinetics,” Antimicrobial Agents and Chemotherapy, vol. 59, 2015, pp. 3864-69. https://doi.org/10.1128/AAC.00343-15
B.M. Potter et al., “Differential CYP 2D6 metabolism alters primaquine pharmacokinetics,” Antimicrobial Agents and Chemotherspy, vol. 59, 2015, pp. 2380-87. https://doi.org/10.1128/AAC.00015-15
S.R. Marcsisin et al., “Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: Implications for the 8-aminoquinoline class of anti-malarial compounds,” Malaria Journal, vol. 13, 2014, p. 2. https://doi.org/10.1186/1475-2875-13-2
S.R. Marcsisin et al., “Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art,” Pharmacology & Therapeutics, vol. 161, 2016, p. 1-10. https://doi.org/10.1016/j.pharmthera.2016.03.011
J.K. Baird, K.E. Battle, R.E. Howes, “Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms,” Malaria Journal, vol. 17, 2018, p. 42. https://dx.doi.org/10.1186%2Fs12936-018-2190-z
G. Camarda et al, “Antimalarial activity of primaquine operates via a two-step biochemical relay,” Nature Communications, vol. 10, art. 3226, 2019. https://doi.org/10.1038/s41467-019-11239-0
60 Degrees Pharmaceuticals Papers on Tafenoquine for Malaria Prophylaxis
In 2018 tafenoquine was approved by the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) for both the treatment of relapsing P. vivax malaria and the prevention of malaria in adults. The 60 Degrees Pharmaceuticals (60P) drug is known as Arakoda® in the U.S. and Kodatef® in Australia. The dosage regimen for Arakoda®/Kodatef® is a 600 mg “loading dose” over three days, followed by 200 mg weekly. This is the same disease regimen used on the 492 tafenoquine subjects in Study 033 involving the 1st Battalion of the Royal Australian Regiment (1 RAR) in East Timor (the remaining 162 were given mefloquine as a comparator drug). The CEO of 60 Degrees Pharmaceuticals, who founded his company while working as a contractor for USAMMDA, was awarded the license for tafenoquine by the U.S. Army in a contract worth more than USD$18 million for registering the drug with the FDA and the TGA. The 60 Degrees Pharmaceuticals application to the FDA was based primarily on the results of the AMI Study 033 tafenoquine prophylaxis trial (60% of the total cohort in the 60P “integrated safety analysis” paper below) involving 654 troops (including both the 492 tafenoquine subjects and the 162 mefloquine subjects) from 1 RAR serving on peacekeeping operations in East Timor 2000-2001. The results of that study are believed to be fraudulent.
A. Novitt-Moreno et al. “Tafenoquine for malaria prophylaxis in adults: An integrated safety analysis,” Travel Medicine and Infectious Diseases, vol. 17, 2017, pp. 19-27. https://doi.org/10.1016/j.tmaid.2017.05.008
GSK/MMV Studies of Tafenoquine for “Radical Cure” of P. vivax Malaria
Some time around 2010, coinciding with the publication of AMI Study 033, GSK discontinued it’s involvement in developing tafenoquine for malaria prophylaxis, ostensibly due to safety concerns for G6PD-deficient individuals. The GSK drug indicated for the treatment of P. vivax malaria, based on a single 300 mg dose sometimes called “radical cure” is known as Krintafel® in the U.S. or Kozenis® in Australia. Notably, these papers make no reference to the earlier AMI tafenoquine PEP studies, which administered dosages of up to 1,209 mg over three days. Regulatory approval of Krintafel® by the FDA entitled GSK to the award of a “priority review voucher”, a saleable product valued at up to USD$350 million, even if a single tablet of this drug is never sold.
- Coming soon.