Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Abstract

dCytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYP mouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.T he 8-aminoquinoline class of antimalarial compounds is the only molecular scaffold with proven efficacy against relapsing strains of malaria (1-5). Currently, the only FDA-approved drug from this class that is available for clinical use is primaquine. Primaquine has been utilized for over 6 decades in treating malaria (6). Despite the long history of primaquine therapy for malaria treatment, primaquine has several disadvantages, including the hemolytic toxicity associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency; its relatively short elimination half-life in humans, which requires daily administration; and the potential requirement for cytochrome P450 (CYP) 2D6-mediated activation for radical curative activity (7-11). The 8-aminoquinoline molecule tafenoquine, currently under late-stage clinical development, has a significantly longer elimination half-life than primaquine (12-16) and has single-dose radical curative activity in humans (3). Tafenoquine is also being developed as a chemoprophylactic agent and has demonstrated efficacy against Plasmodium vivax and Plasmodium falciparum (17)(18)(19)(20)(21). Despite the pharmacological advantages of tafenoquine over primaquine, both molecules seem to have the same pharmacogenomic liability of CYP 2D6-mediated activation for liver-stage antimalarial activity (7,10,22,23) and are not free of hemolytic liability in G6PD def...

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

“…The only other 8-aminoquineoline that is close to fielding and under late stage development for radical cure is tafenoquine. Tafenoquine is a single dose radical curative agent that is a promising alternative to primaquine, however, tafenoquine might also require hepatic metabolism for efficacy as indicated by pre-clinical testing in animal models (Marcsisin, et al, 2014;Vuong, et al, 2015).…”

Cytochrome P450 2D-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of Plasmodium berghei

“…As shown in Table 3, 20 mg/kg TQ led to 100% suppression of the IVIS signal and no detectable erythrocytic infection for 5/5 mice when administered on days −1, 0, and/or +1, while lower doses led to either incomplete suppression of the IVIS signal or failure to eradicate the erythrocytic infections within the dosing cohorts. Given the long half-life of TQ in wild-type mice (plasma t 1/2  = 53.8 ± 3.5 h; liver t 1/2  = 83.5 ± 2.3 h [27]), the causal activity of TQ administered on day −1 is likely related to drug remaining in the liver when sporozoites are inoculated on day 0; the anti-erythrocytic activity in the absence of causal activity of TQ administered on day +1 could be related to drug remaining in the circulation when parasites emerge from the liver on day +3. The administration of 20 mpk day +4 led to the eradication of erythrocytic parasites in 4/5 mice with recrudescence observed in 1/5 mice after 29 days (Table 3).…”

“…2) between WT and KO cohorts treated with TQ for the duration of the study. The prolonged duration prior to recrudescence for the TQ-treated animals is likely related to the longer half-life in plasma (WT t 1/2  = 53.8 ± 3.5 h; CYP2D KO t 1/2  = 72.4 ± 15.5 h) and delayed clearance relative to PQ [27]. …”

“…The error shown is the standard deviation of relative fold changes for KO pharmacokinetic parameters as compared to WT means pharmacokinetic parameter values. PQ and TQ comparisons were conducted using experimental data generated at the WRAIR [26, 27]. WT C57BL/6 wild-type mice.…”

“…Pharmacokinetic (PK) parameters for PQ and TQ in plasma and liver generated by the WRAIR [26, 27] were analysed using noncompartmental analysis (NCA) via the Phoenix-Win-Nonlin software package (version 6.4; Pharsight Corp., Mountain View, CA). The PK parameters were utilized to explore the variability between wild-type and CYP2D knock-out mice.…”