A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

Roma Chilengi, Rashid Juma, Ahmed M Abdallah, Mahfudh Bashraheil, Hudson Lodenyo, Priscilla Nyakundi, Evelyn Anabwani, Amina Salim, Gabriel Mwambingu, Ednah Wenwa, Julie Jemutai, Chemtai Kipkeu, George O Oyoo, Simon N Muchohi, Gilbert Kokwaro, Tim Niehues, Trudie Lang, Alexis Nzila, Roma Chilengi, Rashid Juma, Ahmed M Abdallah, Mahfudh Bashraheil, Hudson Lodenyo, Priscilla Nyakundi, Evelyn Anabwani, Amina Salim, Gabriel Mwambingu, Ednah Wenwa, Julie Jemutai, Chemtai Kipkeu, George O Oyoo, Simon N Muchohi, Gilbert Kokwaro, Tim Niehues, Trudie Lang, Alexis Nzila

Abstract

Background: Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers.

Methods: Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days.

Results: The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was <150 nM.

Conclusion: Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C(eff) of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

Figures

Figure 1
Figure 1
Study flow chart.
Figure 2
Figure 2
Means and stand errors (SE) of serial haematological measurements of hemoglobin (Hb), white blood cell (WBC) and creatine (Cr).
Figure 3
Figure 3
Means and standard errors of serial clinical chemistry measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin (Tot. Bil).
Figure 4
Figure 4
Methotrexate (MTX) plasma concentration from day 0 to day 4. Five participant provided blood each day, thus each point represents a mean of 5 measurements. IC99 represents MTX concentration that inhibits 99% of parasite growth in vitro.

References

    1. WHO. Guidelines for the treatment of malaria. Second. Access on 14 June 2010.
    1. Medicines for malaria venture (MMV) research, development and science-portfolio.
    1. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;10:1647–1657. doi: 10.1016/S0140-6736(10)61924-1.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;10:455–467. doi: 10.1056/NEJMoa0808859.
    1. Okombo J, Ohuma E, Picot S, Nzila A. Update on genetic markers of quinine resistance in Plasmodium falciparum. Mol Biochem Parasitol. 2011. in press .
    1. Kiara SM, Okombo J, Masseno V, Mwai L, Ochola I, Borrmann S, Nzila A. In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation. Antimicrob Agents Chemother. 2009;10:3793–3798. doi: 10.1128/AAC.00308-09.
    1. Dar O, Khan MS, Adagu I. The potential use of methotrexate in the treatment of falciparum malaria: in vitro assays against sensitive and multidrug-resistant falciparum strains. Jpn J Infect Dis. 2008;10:210–211.
    1. Nduati E, Hunt S, Kamau EM, Nzila A. 2,4-diaminopteridine-based compounds as precursors for de novo synthesis of antifolates: a novel class of antimalarials. Antimicrob Agents Chemother. 2005;10:3652–3657. doi: 10.1128/AAC.49.9.3652-3657.2005.
    1. Fidock DA, Nomura T, Wellems TE. Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase. Mol Pharmacol. 1998;10:1140–1147.
    1. Walter RD, Bergmann B, Kansy M, Wiese M, Seydel JK. Pyrimethamin-resistant Plasmodium falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines. Parasitol Res. 1991;10:346–350. doi: 10.1007/BF00930913.
    1. Chabner BA, Amrein P, Drucker B, Michealson M, Mitsiades C, Goss P, Ryan D, Ramachandra S, Richardson P, Supko J, Wilson W. In: The pharmacological basis of therapeutics 9/e. Brunton L, editor. New York: McGrwa-Hill; 2006. Antineoplastic agents; pp. 1315–1465.
    1. Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol. 2009;10:824–837. doi: 10.1016/j.jaad.2008.11.906.
    1. Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 2006;10:473–492.
    1. Niehues T, Lankisch P. Recommendations for the use of methotrexate in juvenile idiopathic arthritis. Paediatric drugs. 2006;10:347–356. doi: 10.2165/00148581-200608060-00003.
    1. Chladek J, Grim J, Martinkova J, Simkova M, Vaneckova J. Low-dose methotrexate pharmacokinetics and pharmacodynamics in the therapy of severe psoriasis. Basic Clin Pharmacol Toxicol. 2005;10:247–248. doi: 10.1111/j.1742-7843.2005.pto960318.x.
    1. Grim J, Chladek J, Martinkova J. Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases. Clin Pharmacokinet. 2003;10:139–151. doi: 10.2165/00003088-200342020-00003.
    1. Chladek J, Grim J, Martinkova J, Simkova M, Vaniekova J, Koudelkova V, Noiekova M. Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of psoriasis. Br J Clin Pharmacol. 2002;10:147–156. doi: 10.1046/j.1365-2125.2002.01621.x.
    1. Wildbolz A. Methotrexate in the therapy of malaria. Ther Umsch. 1973;10:218–222.
    1. Sheehy TW, Dempsey H. Methotrexate therapy for Plasmodium vivax malaria. Jama. 1970;10:109–114. doi: 10.1001/jama.214.1.109.
    1. Nzila A, Okombo J, Becker RP, Chilengi R, Lang T, Niehues T. Anticancer agents against malaria: time to revisit? Trends Parasitol. 2010;10:125–129. doi: 10.1016/j.pt.2009.12.002.
    1. Anonymous. World Medical Association Declaration of Helsinki: ethical principles from medical tresearch involving human subjects. Paragraph 17. Revision adopted by the 59th World Medical Assembly, Seoul. 2008.
    1. ICH-GCP-E6. International Conference on Harmonisation Guidance: Good Clinical Practices. Global Medical Education & Development. 1997.
    1. Visser K, van der Heijde DM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheum. 2009;10:1017–1025.
    1. Fournier MR, Klein J, Minuk GY, Bernstein CN. Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. Am J Gastroenterol. 2010;10:1620–1626. doi: 10.1038/ajg.2010.21.
    1. Tahiri L, Allali F, Jroundi I, Abouqal R, Hajjaj-Hassouni N. [Therapeutic maintenance level of methotrexate in rheumatoid arthritis] Sante. 2006;10:167–172.
    1. Owino BO, Oyoo GO, Otieno CF. Socio-demographic and clinical aspects of rheumatoid arthritis. East Afr Med J. 2009;10:204–211.
    1. Domenech E, Manosa M, Navarro M, Masnou H, Garcia-Planella E, Zabana Y, Cabre E, Gassull MA. Long-term methotrexate for Crohn's disease: safety and efficacy in clinical practice. J Clin Gastroent. 2008;10:395–399. doi: 10.1097/MCG.0b013e31802e6875.
    1. Montero Mora P, Gonzalez Perez Mdel C, Almeida Arvizu V, Matta Campos JJ. [Autoimmune urticaria. Treatment with methotrexate] Rev Alerg Mex. 2004;10:167–172.
    1. Chen J. Is methotrexate effective for the treatment of ankylosing spondylitis? Nature Clin Pract. 2007;10:490–491. doi: 10.1038/ncprheum0566.
    1. Bosman T, Simonin C, Launay D, Caron S, Destee A, Defebvre L. Idiopathic hypertrophic cranial pachymeningitis treated by oral methotrexate: a case report and review of literature. Rheum Intern. 2008;10:713–718. doi: 10.1007/s00296-007-0504-5.
    1. Novak K, Swain MG. Role of methotrexate in the treatment of chronic cholestatic disorders. Clinics Liv Dis. 2008;10:81–96. doi: 10.1016/j.cld.2007.11.011.
    1. Specks U. Methotrexate for Wegener's granulomatosis: what is the evidence? Arthritis Rheum. 2005;10:2237–2242. doi: 10.1002/art.21146.
    1. Gong Y, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2005. p. CD004385.
    1. Wong JM, Esdaile JM. Methotrexate in systemic lupus erythematosus. Lupus. 2005;10:101–105. doi: 10.1191/0961203305lu2043rr.
    1. Stawell R. Methotrexate in inflammatory eye disease. Oc Immunol Inflam. 2003;10:79–82. doi: 10.1076/ocii.11.2.79.15918.
    1. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediat Blood Cancer. 2007;10:124–131. doi: 10.1002/pbc.21039.
    1. Nduati E, Diriye A, Ommeh S, Mwai L, Kiara S, Masseno V, Kokwaro G, Nzila A. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. Parasitol Res. 2008;10:1227–1234. doi: 10.1007/s00436-008-0897-4.

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