The blood schizonticidal activity of tafenoquine makes an essential contribution to its prophylactic efficacy in nonimmune subjects at the intended dose (200 mg)

Geoffrey Dow, Bryan Smith, Geoffrey Dow, Bryan Smith

Abstract

Tafenoquine (TQ) is an 8-aminoquinoline anti-malarial being developed for malaria prophylaxis. It has been generally assumed that TQ, administered prophylactically, acts primarily on the developing exoerythrocytic stages of malaria parasites (causal prophylaxis), and that polymorphisms in metabolic enzymes thought to impact the activity of other 8-aminoquinolines also inhibit this property of TQ. Furthermore, it has been suggested that a diagnostic test for CYP2D6 metabolizer status might be required. In field studies in which metabolic status was not an exclusion criteria, TQ has been shown to exhibit similar prophylactic efficacy as blood schizonticidal drugs (mefloquine). Also, its blood schizonticidal and anti-relapse efficacy is independent of 2D6 metabolizer status. The most reasonable explanation for the field study results, supported by other clinical and non-clinical data, is that TQ is not completely causal and exhibits substantial blood schizonticidal activity at the intended dose. Pharmacokinetic simulations demonstrate that trough concentrations of TQ exceed the proposed MIC of 80 ng/ml in >95% of individuals. Based on these data a companion diagnostic for CP450 enzyme status is not required.

Keywords: Antimalarial drug; Asexual blood stages; Blood schizonticide; Malaria; Plasmodium falciparum; Plasmodium vivax; Primaquine; Tafenoquine.

Figures

Fig. 1
Fig. 1
Plasma-concentration time curves for selected regimens of tafenoquine. Plasma-concentration time curves for tafenoquine generated from pharmacokinetic simulations at doses of 200 mg (a) and 100 mg (b) administered once per day for 3 days (load) then once per week for a simulated deployment of 6 months. Median trough concentrations exceed the putative MIC of 80 ng/ml for both regimens, but trough levels for the 200 mg dose exceed the MIC in 95% of subjects. The simulations utilized pharmacokinetic parameters from a US Army study [16] which were derived from modeling of data from eleven published and unpublished pharmacokinetic studies

References

    1. Deye GA, Magill JA. Primaquine for prophylaxis of malaria: has the CYP sailed? J Travel Med. 2014;21:67–69. doi: 10.1111/jtm.12080.
    1. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg. 2006;75:402–415.
    1. Arnold J, Alving AS, Hockwald RS, Clayman CB, Dern RJ, Beutler E, et al. The antimalarial action of primaquine against the blood and tissue stages of falciparum malaria (Panama, P-F-6 strain) J Lab Clin Med. 1955;46:391–397.
    1. Arnold J, Alving AS, Hockwald RS, Clayman CB, Dern RJ, Beutler E, et al. The effect of continuous and intermittent primaquine therapy on the relapse rate of Chesson strain vivax malaria. J Lab Clin Med. 1954;44:429–438.
    1. Baird JK, Wiady I, Sutanihardja A, Suradi Purnomo, Basri H, et al. Short report: therapeutic efficacy of chloroquine combined with primaquine against Plasmodium falciparum in northeastern Papua, Indonesia. Am J Trop Med Hyg. 2002;66:659–660. doi: 10.4269/ajtmh.2002.66.659.
    1. Pukrittayakamee S, Vanijanonta S, Chantra A, Clemens R, White NJ. Blood stage antimalarial efficacy of primaquine in Plasmodium vivax malaria. J Infect Dis. 1994;169:932–935. doi: 10.1093/infdis/169.4.932.
    1. Bennett JW, Pybus BS, Yadava A, Tosh D, Sousa JC, McCarthy WF, et al. Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria. N Engl J Med. 2013;369:1381–1382. doi: 10.1056/NEJMc1301936.
    1. Pybus BS, Marcsisin SR, Jin X, Deye G, Sousa JC, Li Q, et al. The metabolism of primaquine to its active metabolite is dependent on CYP 2D6. Malar J. 2013;12:212. doi: 10.1186/1475-2875-12-212.
    1. Sistonena J, Sajantilaa A, Laoc O, Coranderb J, Barbujanid G, Fusellia S. CYP2D6 worldwide genetic variation shows high frequency of altered activity and no continental structure. Pharmacogenet Genom. 2007;17:93–101.
    1. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002;3:229–243. doi: 10.1517/14622416.3.2.229.
    1. Dow GS, McCarthy WF, Reid M, Smith B, Tang D, Shanks GD. A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic anti-malarials in non-immune individuals during deployment to a malaria-endemic area. Malar J. 2014;13:49. doi: 10.1186/1475-2875-13-49.
    1. Dow GS, Liu J, Lin G, Hetzell B, Thieling S, McCarthy WF, et al. Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries. Malar J. 2015;14:473. doi: 10.1186/s12936-015-0991-x.
    1. Li Q, O’Neil M, Xie L, Caridha D, Zeng Q, Zang Q, et al. Assessment of the prophylactic activity and pharmacokinetic profile of oral tafenoquine compared to primaquine for inhibition of liver stage malaria infections. Malar J. 2014;13:141. doi: 10.1186/1475-2875-13-141.
    1. Brueckner RP, Coster T, Wesche DL, Shmuklarsky M, Schuster BG. Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial. Antimicrob Agents Chemother. 1998;42:1293–1294.
    1. Dow GS, Gettayacamin M, Hansukjariya P, Imerbsin R, Komcharoen S, Sattabongkot J, et al. Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected rhesus monkeys (Macaca mulatta) Malar J. 2011;10:212. doi: 10.1186/1475-2875-10-212.
    1. US Army. Population pharmacokinetic modeling of tafenoquine. Final Report, 2013. Report available on request.
    1. Obaldia N, 3rd, Rossan RN, Cooper RD, Kyle DE, Nuzum EO, Rieckmann KH, et al. WR 238605, chloroquine, and their combinations as blood schizonticides against a chloroquine-resistant strain of Plasmodium vivax in Aotus monkeys. Am J Trop Med Hyg. 1997;56:508–510. doi: 10.4269/ajtmh.1997.56.508.
    1. Edstein MD, Kocisko DA, Walsh DS, Eamsila C, Charles BG, Rieckmann KH. Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis. Clin Infect Dis. 2003;37:1654–1658. doi: 10.1086/379718.
    1. Walsh DS, Eamsila C, Sasiprapha T, Sangkharomya S, Khaewsathien P, Supakalin P, et al. Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P. falciparum malaria. J Infect Dis. 2004;190:1456–1463. doi: 10.1086/424468.
    1. Peters W, Robinson BL, Milhous WK. The chemotherapy of rodent malaria. LI. Studies on a new 8-aminoquinoline, WR238605. Ann Trop Med Parasitol. 1993;87:547–552. doi: 10.1080/00034983.1993.11812809.
    1. Milner EE, Berman J, Caridha D, Dickson SP, Hickman M, Lee PJJ, et al. Cytochrome P450 2D-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of Plasmodium berghei. Malar J. 2016;15:558. doi: 10.1186/s12936-016-1632-8.
    1. Ramharter M, Noedl H, Thimasarn K, Wiedermann G, Wernsdorfer G, Wernsdorfer WH. In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum. Am J Trop Med Hyg. 2002;67:39–43. doi: 10.4269/ajtmh.2002.67.39.
    1. Ohrt C, Willingmyre GD, Lee P, Knirsch C, Milhous W. Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. 2002;46:2518–2524. doi: 10.1128/AAC.46.8.2518-2524.2002.
    1. Pradines B, Mamfoumbi MM, Tall A, Sokhna C, Koeck JL, Fusai T, et al. In vitro activity of tafenoquine against the asexual blood stages of Plasmodium falciparum isolates from Gabon, Senegal, and Djibouti. Antimicrob Agents Chemother. 2006;50:3225–3226. doi: 10.1128/AAC.00777-06.
    1. Vennerstrom JL, Nuzum EO, Miller RE, Dorn A, Gerena L, Dande PA, et al. 8-Aminoquinoline derivatives against blood stage Plasmodium falciparum in vitro inhibit hematin polymerization. Antimicrob Agents Chemother. 1999;42:598–602.
    1. Salvidio E, Pannacciulli I, Tizianello A, Ajmar F. Nature of hemolytic crises and the fate of G6PD deficient drug-damaged erythrocytes in Sardinians. New Eng J Med. 1967;276:1339. doi: 10.1056/NEJM196706152762402.
    1. Hopkins J, Tudhope GR. The effects of drugs on erythrocytes in vitro: heinz body formation, glutathione peroxidase inhibition and changes in mechanical fragility. Br J Clin Pharmacol. 1974;1:191–195. doi: 10.1111/j.1365-2125.1974.tb00235.x.
    1. St Jean PL, Xue Z, Carter N, Koh GC, Duparc S, Taylor M, et al. Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 is not associated with relapse in the Phase 2b DETECTIVE trial. Malar J. 2016;15:97. doi: 10.1186/s12936-016-1145-5.
    1. Nasveld PE, Edstein MD, Reid M, Harris IE, Kitchener SJ, Leggat PA, et al. Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. Antimicrob Agents Chemother. 2010;54:792–798. doi: 10.1128/AAC.00354-09.
    1. Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, et al. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicenter, double-blind, randomized, phase 2b dose-selection study. Lancet. 2014;383:1049–1058. doi: 10.1016/S0140-6736(13)62568-4.
    1. Newby G, Hwang J, Koita K, Chen I, Greenwood B, von Seidlein L, et al. Review of mass drug administration for malaria and its operational challenges. Am J Trop Med Hyg. 2015;93:125–134. doi: 10.4269/ajtmh.14-0254.

Source: PubMed

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