Clinical pharmacokinetics of methotrexate in the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma in pediatric patients
Abstract
Metotreksat (MTX) se u visokim dozama koristi u terapiji akutne limfoblastne leukemije i ne-Hodkinovog limfoma u pedijatrijskoj populaciji. Deluje kao kompetitivni inhibitor dihidrofolat reduktaze i time inhibira sintezu deoksiribonukleinske kiseline. Stepen biološke raspoloživosti zavisi od puta primene leka i doze. Vezivanje za proteine plazme je u umerenom stepenu, a raspodeljuje se u tkiva i ćelije. Nakon primene u visokim dozama MTX delimično podleže hepatičkom i intracelularnom metabolizmu, ali glavni put eliminacije je preko bubrega u nepromenjenom obliku. Veliki broj faktora utiče na farmakokinetiku i koncentraciju leka, a pre svega je opisan uticaj funkcije bubrega na eliminaciju. Usporena eliminacija može biti i posledica interakcije sa drugim lekovima na nivou transportera u renalnim tubulima. Primena visokih doza MTX nosi rizik od pojave toksičnosti, posebno pri usporenoj eliminaciji. Terapijsko praćenje leka je indikovano iz bezbednosnih razloga, kako bi se optimizovala primena leukovorina (folinska kiselina) koji smanjuje toksičnost MTX. Imajući u vidu varijabilnost i toksičnost pri primeni visokih doza MTX poseban oprez je potreban u pedijatrijskoj populaciji pacijenata.
References
Rahman LKA, Chhabra SR. The chemistry of methotrexate and its analogues. Med Res Rev. 1988;8(1):95–155.
Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41(1):36–51.
Adam de Beaumais T, Jacqz-Aigrain E. Intracellular Disposition of Methotrexate in Acute Lymphoblastic Leukemia in Children. Curr Drug Metab. 2012;13(6):822–34.
Ylinen E, Jahnukainen K, Saarinen-Pihkala UM, Jahnukainen T. Assessment of renal function during high-dose methotrexate treatment in children with acute lymphoblastic leukemia: Effect of HD-Methotrexate on Renal Function. Pediatr Blood Cancer. 2014;61(12):2199–202.
Mao J, Zhang L, Shen H, Tang Y, Song H, Zhao F, et al. Creatinine clearance rate and serum creatinine concentration are related to delayed methotrexate elimination in children with lymphoblastic malignancies. Neoplasma. 2014;61(01):77–82.
Sažetak karakteristika leka, Leucovorin® Kalcijum 50 mg/5 mL rastvor za injekciju, datum revizije teksta- Novembar 2013. Dostupno na: https://www.alims.gov.rs/wp-content/blogs.dir/2/files/lekovi/smpc/515-01-05623-13-001.pdf Pristupljeno: Oktobar 2019.
Treon P, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem. 1996; 42 (8 (2)):1322-9.
Skarby Tvc, Anderson H, Heldrup J, Kanerva J, Seidel H, Schmiegelow K. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia. 2006 ;20(11):1955-62.
Moore MJ, Erlichman C. Therapeutic drug monitoring in oncology. Problems and potential in antineoplastic therapy. Clin Pharmacokinet. 1987;13(4):205-27.
Kodidela S, Suresh Chandra P, Dubashi B. Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level? Eur J Clin Pharmacol. 2014;70(3):253–60.
Green MR, Chowdhary S, Lombardi KM, Chalmers LM, Chamberlain M. Clinical utility and pharmacology of high-dose methotrexate in the treatment of primary CNS lymphoma. Expert Rev Neurother. 2006;6(5):635–52.
Teresi ME, Crom WR, Choi KE, Mirro J, Evans WE. Methotrexate bioavailability after oral and intramuscular administration in children. J Pediatr. 1987;110(5):788–92.
Kozloski GD, De Vito JM, Kisicki JC, Johnson JB. The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers. Arthritis Rheum. 1992;35(7):761–4.
Balis FM, Mirro J, Reaman GH, Evans WE, McCully C, Doherty KM, et al. Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol. 1988;6(12):1882–6.
Shen DD, Azarnoff DL. Clinical Pharmacokinetics of Methotrexate1: Clin Pharmacokinet. 1978;3(1):1–13.
Mei S, Li X, Jiang X, Yu K, Lin S, Zhao Z. Population Pharmacokinetics of High-Dose Methotrexate in Patients With Primary Central Nervous System Lymphoma. J Pharm Sci. 2018;107(5):1454–60.
Sažetak karakteristika leka, metotreksat, 100 mg/mL, koncentrat za rastvor za infuziju. (engl. Methotrexate 100 mg/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC)) - (emc) [internet]. [pristupljeno 30. oktobar 2019.]. Dostupno na: https://www.medicines.org.uk/emc/product/6845/smpc#INTERACTIONS
Schrøder H, Fogh K, Herlin T. In vivo decline of methotrexate and methotrexate polyglutamates in age-fractionated erythrocytes. Cancer Chemother Pharmacol. 1988; 21:150-5.
Borsi JD, Sagen E, Ing C, Romslo I, Moe PJ. Pharmacokinetics and Metabolism of Methotrexate: An Example for the Use of Clinical Pharmacology in Pediatric Oncology. Pediatr Hematol Oncol. 1990;7(1):13–33.
Wang Y-M, Fujimoto T. Clinical Pharmacokinetics of Methotrexate in Children: Clin Pharmacokinet. 1984;9(4):335–48.
Csordas K, Hegyi M, Eipel OT, Muller J, Erdelyi DJ, Kovacs GT. Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia: Anticancer Drugs. 2013;24(2):189–97.
Borsi JD, Moe PJ. A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 g to 33.6 g/m2 in children with acute lymphoblastic leukemia. Cancer. 1987;60(1):5–13.
Li J, Gwilt P. The effect of malignant effusions on methotrexate disposition. Cancer Chemother Pharmacol. 2002.;50(5):373–82.
Levêque D, Becker G, Toussaint E, Fornecker L-M, Paillard C. Clinical pharmacokinetics of methotrexate in oncology. Int J Pharmacokinet. 2017;2(2):137–47.
Evans WE, Crom WR, Sinkule JA, Yee GC, Stewart CF, Hutson PR. Pharmacokinetics of Anticancer Drugs in Children. Drug Metab Rev. 1983; 14 (5): 847-86.
Levêque D, Santucci R, Gourieux B, Herbrecht R. Pharmacokinetic drug–drug interactions with methotrexate in oncology. Expert Rev Clin Pharmacol. 2011; 4(6):743–50.
Donelli MG, Zucchetti M, Robatto L, Perlangeli V, D’Incalci M, Masera G, et al. Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. Med Pediatr Oncol. 1995;24(3):154–9.
Thompson PA, Murry DJ, Rosner GL, Lunagomez S, Blaney SM, Berg SL, et al. Methotrexate pharmacokinetics in infants with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 19. Март 2007.;59(6):847–53.
Beechinor RJ, Thompson PA, Hwang MF, Vargo RC, Bomgaars LR, Gerhart JG, et al. The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children’s Oncology Group. Clin Pharmacokinet. 2019;58(7):899–910.
Rühs H, Becker A, Drescher A, Panetta JC, Pui C-H, Relling MV, et al. Population PK/PD Model of Homocysteine Concentrations after High-Dose Methotrexate Treatment in Patients with Acute Lymphoblastic Leukemia. PLoS ONE. 2012;7(9):e46015.
Wright KD, Panetta JC, Onar-Thomas A, Reddick WE, Patay Z, Qaddoumi I, et al. Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections. Cancer Chemother Pharmacol. 2015;75(1):27–35.
Paci A, Veal G, Bardin C, Levêque D, Widmer N, Beijnen J, и остали. Review of therapeutic drug monitoring of anticancer drugs part 1 – Cytotoxics. Eur J Cancer. 2014.;50(12):2010–9.
Protokol kliničkog ispitvanja, ALL IC-BFM-2009. Dostupno na: http://www.bialaczka.org/wp-content/uploads/2016/10/ALLIC_BFM_2009.pdf. Pristupljeno avgusta 2019.
Skarby T, Jonsson P, Hjorth L, Behrentz M, Bjork O, Forestier E et al. High-dose methotrexate: on relatationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acuzte lymphoblastic leukemia (ALL). Cancer Chemother Pharmacol. 2003; 51(4): 311-20.
Jönsson P, Skärby T, Heldrup J, Schrøder H, Höglund P. High dose methotrexate treatment in children with acute lymphoblastic leukaemia may be optimised by a weight-based dose calculation. Pediatr Blood Cancer. 2011;57(1):41–6.
Bezabeh S, Mackey AC, Kluetz P, Jappar D, Korvick J. Accumulating Evidence for a Drug-Drug Interaction Between Methotrexate and Proton Pump Inhibitors. The Oncologist. 2012.;17(4):550–4.
von Stackelberg A, Hartmann R, Bührer C, Fengler R, Janka-Schaub G, Reiter A, и остали. High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood. 2008;111(5):2573–80.
Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, et al. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009;67(1):44–9.
Schmiegelow K. Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol. 2009.;146(5):489–503.
Cohen IJ. Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue. Cancer Chemother Pharmacol. 2017;79(6):1057–65.
Mikkelsen TS, Mamoudou AD, Tuckuviene R, Wehner PS, Schroeder H. Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions: A prospectively randomized cross-over study: Prehydration for High-Dose Methotrexate. Pediatr Blood Cancer. 2014;61(2):297–301.
Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and Clinical Aspects of Methotrexate Neurotoxicity. Chemotherapy. 2003;49(1–2):92–104.
Lexicomp: Interakcije (eng. Interactions) [internet]. [pristupljeno 02. decembra 2019.]. Dostupno na: https://online.lexi.com/lco/action/interact
