Skip to main content

Advertisement

SpringerLink
Log in

Factors influencing methotrexate pharmacokinetics highlight the need for individualized dose adjustment: a systematic review

  • Review
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine covariates affecting MTX disposition.

Methods

We compared MTX PK profiles among neonates, children, and adults by performing a systematic literature search for published population MTX models and conducted a Monte Carlo-based meta-analysis. Subsequently, we evaluated study quality and covariates significantly affecting dosage regimens and compared LDMTX and HDMTX PK profiles.

Results

Of the total 40 studies included, 34 were HDMTX, and six were LDMTX studies. For HDMTX, three studies involving neonates reported estimated apparent clearances (median, range) of 0.53 (0.27–0.77) L/kg/h; for 14 studies involving children, 0.23 (0.07–0.23) L/kg/h; and for 13 involving adults, 0.11 (0.03–0.22) L/kg/h. Neonates had a higher volume of distribution than children and adults. For LDMTX studies, apparent clearance was 0.085 (0.05–1.68) L/kg/h, and volume of distribution was 0.25 (0.018–0.47) L/kg, lower than those of HDMTX studies, with large between-subject variability. Bodyweight significantly influenced apparent clearance and volume of distribution, whereas renal function mainly influenced clearance. Mutations in certain genes reduced MTX clearance by 8–35.3%, whereas those in others increased it by 15–48%. Body surface area (BSA) significantly influenced apparent clearance with a median reduction of 51% when BSA increased in pediatric patients.

Conclusions

Methotrexate dosage regimens were primarily based on body surface area and renal function. Further studies are needed to evaluate MTX pharmacokinetics and pharmacodynamics in both children (especially infants) and adults.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Guichard N, Guillarme D, Bonnabry P, Fleury-Souverain S (2017) Antineoplastic drugs and their analysis: a state of the art review. Analyst 142:2273–2321. https://doi.org/10.1039/c7an00367f

    Article  CAS  PubMed  Google Scholar 

  2. Cronstein BN (1996) Molecular therapeutics. methotrexate and its mechanism of action. Arthritis Rheum 39:1951–1960. https://doi.org/10.1002/art.1780391203

    Article  CAS  PubMed  Google Scholar 

  3. Taylor ZL, Vang J, Lopez-Lopez E, Oosterom N, Mikkelsen T, Ramsey LB (2021) Systematic review of pharmacogenetic factors that influence high-dose methotrexate pharmacokinetics in pediatric malignancies. Cancers (Basel) 13:2837. https://doi.org/10.3390/cancers13112837

    Article  CAS  PubMed  Google Scholar 

  4. Methotrexate (Jiangsu Hengrui Pharmaceutical Co., LTD): drug information

  5. Weinblatt ME, Trentham DE, Fraser PA, Holdsworth DE, Falchuk KR, Weissman BN, Coblyn JS (1988) Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum 31:167–175. https://doi.org/10.1002/art.1780310203

    Article  CAS  PubMed  Google Scholar 

  6. Morgan C, Lunt M, Brightwell H, Bradburn P, Fallow W, Lay M, Silman A, Bruce IN (2003) Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis 62:15–19. https://doi.org/10.1136/ard.62.1.15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. American Society of Clinical Oncology, Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow GR, Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM (2006) American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24:2932–2947. https://doi.org/10.1200/JCO.2006.06.9591

    Article  CAS  Google Scholar 

  8. Ramsey LB, Balis FM, MM, Schmiegelow K, Pauley JL, Bleyer A, Widemann BC, Askenazi D, Bergeron S, Shirali A, Schwartz S, Vinks AA, Heldrup J, (2018) Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Oncologist 23:52–61. https://doi.org/10.1634/theoncologist.2017-0243

    Article  CAS  PubMed  Google Scholar 

  9. Shen DD, Azarnoff DL (1978) Clinical pharmacokinetics of methotrexate. Clin Pharmacokinet 3:1–13. https://doi.org/10.2165/00003088-197803010-00001

    Article  CAS  PubMed  Google Scholar 

  10. Paci A, Veal G, Bardin C, Levêque D, Widmer N, Beijnen J, Astier A, Chatelut E (2014) Review of therapeutic drug monitoring of anticancer drugs part 1 – cytotoxics. Eur J Cancer 50:2010–2019. https://doi.org/10.1016/j.ejca.2014.04.014

    Article  CAS  PubMed  Google Scholar 

  11. Holmboe L, Andersen AM, Mørkrid L, Slørdal L, Hall KS (2012) High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients. Br J Clin Pharmacol 73:106–114. https://doi.org/10.1111/j.1365-2125.2011.04054.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sabot C, Debord J, Roullet B, Marquet P, Merle L, Lachatre G (1995) Comparison of 2- and 3-compartment models for the Bayesian estimation of methotrexate pharmacokinetics. Int J Clin Pharmacol Ther 33:164–169

    CAS  PubMed  Google Scholar 

  13. Sheiner LB, Rosenberg B, Melmon KL (1972) Modelling of individual pharmacokinetics for computer-aided drug dosage. Comput Biomed Res 5:411–459. https://doi.org/10.1016/0010-4809(72)90051-1

    Article  CAS  PubMed  Google Scholar 

  14. Lu X, Xu G, Chen L, Fan J, Li M, Zhu L (2020) Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations. Eur J Clin Pharmacol 76:695–702. https://doi.org/10.1007/s00228-020-02840-0

    Article  CAS  PubMed  Google Scholar 

  15. Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M, German-Austrian-Swiss ALL-BFM Study Group (2008) Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111:4477–4489. https://doi.org/10.1182/blood-2007-09-112920

    Article  CAS  Google Scholar 

  16. Reiter A, Tiemann M, Ludwig WD, Wacker HH, Yakisan E, Schrappe M, Henzler D, Sykora KW, Brandt A, Odenwald E (1994) NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin’s lymphomas in children and adolescents. Part 1: classification and allocation to strategic therapy groups. BIF study group Klin Pädiatr 206:222–233. https://doi.org/10.1055/s-2008-1046608

    Article  CAS  Google Scholar 

  17. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C (1995) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 332:901–906. https://doi.org/10.1056/NEJM199504063321401

    Article  CAS  PubMed  Google Scholar 

  18. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nademanee AP, Negrin RS, O’Donnell MR, Parker PM, Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman SJ (1993) Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med 329:1225–1230. https://doi.org/10.1056/NEJM199310213291703

    Article  CAS  PubMed  Google Scholar 

  19. Tugwell P, Bennett K, Gent M (1987) Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann Intern Med 107:358–366. https://doi.org/10.7326/0003-4819-107-2-358

    Article  CAS  PubMed  Google Scholar 

  20. Uemura O, Honda M, Matsuyama T, Ishikura K, Hataya H, Yata N, Nagai T, Ikezumi Y, Fujita N, Ito S, Iijima K, Kitagawa T (2011) Age, gender, and body length effects on reference serum creatinine levels determined by an enzymatic method in Japanese children: a multicenter study. Clin Exp Nephrol 15:694–699. https://doi.org/10.1007/s10157-011-0452-y

    Article  CAS  PubMed  Google Scholar 

  21. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41. https://doi.org/10.1159/000180580

    Article  CAS  PubMed  Google Scholar 

  22. Burns DR, Elswick RK (2001) Equivalence testing with dental clinical trials. J Dent Res 80:1513–1517. https://doi.org/10.1177/00220345010800060701

    Article  CAS  PubMed  Google Scholar 

  23. Wright KD, Stewart CF (2015) Response to: comment on ‘Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections.’ Cancer Chemother Pharmacol 75:877–878. https://doi.org/10.1007/s00280-015-2699-6

    Article  PubMed  Google Scholar 

  24. Beechinor RJ, Thompson PA, Hwang MF, Vargo RC, Bomgaars LR, Gerhart JG, Dreyer ZE, Gonzalez D (2019) 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 58:899–910. https://doi.org/10.1007/s40262-018-00734-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Panetta JC, Roberts JK, Huang J, Lin T, Daryani VM, Harstead KE, Patel YT, Onar-Thomas A, Campagne O, Ward DA, Broniscer A, Robinson G, Gajjar A, Stewart CF (2020) Pharmacokinetic basis for dosing high-dose methotrexate in infants and young children with malignant brain tumours. Br J Clin Pharmacol 86:362–371. https://doi.org/10.1111/bcp.14160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shi ZY, Liu YO, Gu HY, Xu XQ, Yan C, Yang XY, Yan D (2020) Population pharmacokinetics of high-dose methotrexate in Chinese pediatric patients with medulloblastoma. Biopharm Drug Dispos 41:101–110. https://doi.org/10.1002/bdd.2221

    Article  CAS  PubMed  Google Scholar 

  27. Faltaos DW, Hulot JS, Urien S, Morel V, Kaloshi G, Fernandez C, Xuan K, Leblond V, Lechat P (2006) Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy. Cancer Chemother Pharmacol 58:626–633. https://doi.org/10.1007/s00280-006-0202-0

    Article  CAS  PubMed  Google Scholar 

  28. Fukuhara K, Ikawa K, Morikawa N, Kumagai K (2008) Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data. J Clin Pharm Ther 33:677–684. https://doi.org/10.1111/j.1365-2710.2008.00966.x

    Article  CAS  PubMed  Google Scholar 

  29. Min Y, Qiang F, Peng L, Zhu Z (2009) High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy. Biopharm Drug Dispos 30:437–447. https://doi.org/10.1002/bdd.678

    Article  CAS  PubMed  Google Scholar 

  30. Simon N, Marsot A, Villard E, Choquet S, Hoang-Xuan K, Zahr N, Lechat P, Leblond V, Hulot JS (2013) Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy. Pharmacogenom J13:507–513. https://doi.org/10.1038/tpj.2012.37

    Article  CAS  Google Scholar 

  31. Benz-de Bretagne I, Zahr N, Le Gouge A, Hulot JS, Houillier C, Hoang-Xuan K, Gyan E, Lissandre S, Choquet S, Le Guellec C (2014) Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance. Br J Clin Pharmacol 78:329–342. https://doi.org/10.1111/bcp.12326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Watanabe M, Fukuoka N, Takeuchi T, Yamaguchi K, Motoki T, Tanaka H, Kosaka S, Houchi H (2014) Developing population pharmacokinetic parameters for high-dose methotrexate therapy: implication of correlations among developed parameters for individual parameter estimation using the Bayesian least-squares method. Biol Pharm Bull 37:916–921. https://doi.org/10.1248/bpb.b13-00672

    Article  CAS  PubMed  Google Scholar 

  33. Nader A, Zahran N, Alshammaa A, Altaweel H, Kassem N, Wilby KJ (2017) Population pharmacokinetics of intravenous methotrexate in patients with hematological malignancies: utilization of routine clinical monitoring parameters. Eur J Drug Metab Pharmacokinet 42:221–228. https://doi.org/10.1007/s13318-016-0338-1

    Article  CAS  PubMed  Google Scholar 

  34. Mei S, Li X, Jiang X, Yu K, Lin S, Zhao Z (2018) Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma. J Pharm Sci 107:1454–1460. https://doi.org/10.1016/j.xphs.2018.01.004

    Article  CAS  PubMed  Google Scholar 

  35. Yang L, Wu H, de Winter BCM, Sheng CC, Qiu HQ, Cheng Y, Chen J, Zhao QL, Huang J, Jiao Z, Xie RX (2020) Pharmacokinetics and pharmacogenetics of high-dose methotrexate in Chinese adult patients with non-Hodgkin lymphoma: a population analysis. Cancer Chemother Pharmacol 85:881–897. https://doi.org/10.1007/s00280-020-04058-4

    Article  CAS  PubMed  Google Scholar 

  36. Pai MP, Debacker KC, Derstine B, Sullivan J, Su GL, Wang SC (2020) Comparison of body size, morphomics, and kidney function as covariates of high-dose methotrexate clearance in obese adults with primary central nervous system lymphoma. Pharmacotherapy 40:308–319. https://doi.org/10.1002/phar.2379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gallais F, Oberic L, Faguer S, Tavitian S, Lafont T, Marsili S, Brice A, Chatelut E, Puisset F (2021) Body surface area dosing of high-dose methotrexate should be reconsidered, particularly in overweight, adult patients. Ther Drug Monit 43:408–415. https://doi.org/10.1097/FTD.0000000000000813

    Article  CAS  PubMed  Google Scholar 

  38. Arshad U, Taubert M, Seeger-Nukpezah T, Ullah S, Spindeldreier KC, Jaehde U, Hallek M, Fuhr U, Vehreschild JJ, Jakob C (2021) Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients. BMC Cancer 21:719. https://doi.org/10.1186/s12885-021-08443-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Isono T, Hira D, Morikochi A, Fukami T, Ueshima S, Nozaki K, Terada T, Morita SY (2021) Urine volume to hydration volume ratio is associated with pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma. Pharmacol Res Perspect 9:e00883. https://doi.org/10.1002/prp2.883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mao J, Li Q, Li P, Qin W, Chen B, Zhong M (2022) Evaluation and application of population pharmacokinetic models for identifying delayed methotrexate elimination in patients with primary central nervous system lymphoma. Front Pharmacol 13:817673. https://doi.org/10.3389/fphar.2022.817673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, García MJ (2006) Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinet 45:1227–1238. https://doi.org/10.2165/00003088-200645120-00007

    Article  CAS  PubMed  Google Scholar 

  42. Colom H, Farré R, Soy D, Peraire C, Cendros JM, Pardo N, Torrent M, Domenech J, Mangues MA (2009) Population pharmacokinetics of high-dose methotrexate after intravenous administration in pediatric patients with osteosarcoma. Ther Drug Monit 31:76–85. https://doi.org/10.1097/FTD.0b013e3181945624

    Article  CAS  PubMed  Google Scholar 

  43. Faganel Kotnik B, Grabnar I, Bohanec Grabar P, Dolžan V, Jazbec J (2011) Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 67:993–1006. https://doi.org/10.1007/s00228-011-1046-z

    Article  CAS  PubMed  Google Scholar 

  44. Desoky ESE, Ghazal MH, Singh RP, Abdelhamid ON, Derendorf H (2013) Population pharmacokinetics of methotrexate in Egyptian children with lymphoblastic leukemia. Pharmacol Pharm 4:139–145. https://doi.org/10.4236/pp.2013.42020

    Article  CAS  Google Scholar 

  45. Hui KH, Chu HM, Fong PS, Cheng WTF, Lam TN (2019) Population pharmacokinetic study and individual dose adjustments of high-dose methotrexate in Chinese pediatric patients with acute lymphoblastic leukemia or osteosarcoma. J Clin Pharmacol 59:566–577. https://doi.org/10.1002/jcph.1349

    Article  CAS  PubMed  Google Scholar 

  46. Lui G, Treluyer JM, Fresneau B, Piperno-Neumann S, Gaspar N, Corradini N, Gentet JC, Marec Berard PM, Laurence V, Schneider P, Entz-Werle N, Pacquement H, Millot F, Taque S, Freycon C, Lervat C, Le Deley MC, Mahier Ait Oukhatar C, Brugieres L, Le Teuff G, Bouazza N, Sarcoma Group of UNICANCER (2018) A pharmacokinetic and pharmacogenetic analysis of osteosarcoma patients treated with high-dose methotrexate: data from the OS2006/Sarcoma-09 trial. J Clin Pharmacol 58:1541–1549. https://doi.org/10.1002/jcph.1252

    Article  CAS  Google Scholar 

  47. Zang YN, Wang SZ, Qin Y, Zhang JR, Zhao LB, Wang XL (2019) Population pharmacokinetic study of delayed methotrexate excretion in children with acute lymphoblastic leukemia. Int J Clin Pharmacol Ther 57:402–407. https://doi.org/10.5414/CP203423

    Article  CAS  PubMed  Google Scholar 

  48. Medellin-Garibay SE, Hernández-Villa N, Correa-González LC, Morales-Barragán MN, Valero-Rivera KP, Reséndiz-Galván JE, Ortiz-Zamudio JJ, Milán-Segovia RDC, Romano-Moreno S (2020) Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 85:21–31. https://doi.org/10.1007/s00280-019-03977-1

    Article  CAS  PubMed  Google Scholar 

  49. Taylor ZL, Mizuno T, Punt NC, Baskaran B, Navarro Sainz A, Shuman W, Felicelli N, Vinks AA, Heldrup J, Ramsey LB (2020) MTXPK.org: a clinical decision support tool evaluating high-dose methotrexate pharmacokinetics to inform post-infusion care and use of glucarpidase. MTXPK.org. Clin Pharmacol Ther 108:635–643. https://doi.org/10.1002/cpt.1957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gao X, Qian XW, Zhu XH, Yu Y, Miao H, Meng JH, Jiang JY, Wang HS, Zhai XW (2021) Population pharmacokinetics of high-dose methotrexate in Chinese pediatric patients with acute lymphoblastic leukemia. Front Pharmacol 12:701452. https://doi.org/10.3389/fphar.2021.701452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhan M, Sun Y, Zhou F, Wang H, Chen Z, Yan L, Li X (2022) Population pharmacokinetics of methotrexate in paediatric patients with acute lymphoblastic leukaemia and malignant lymphoma. Xenobiotica 52:265–273. https://doi.org/10.1080/00498254.2022.2069060

    Article  CAS  PubMed  Google Scholar 

  52. Johansson ÅM, Hill N, Perisoglou M, Whelan J, Karlsson MO, Standing JF (2011) A population pharmacokinetic/pharmacodynamic model of methotrexate and mucositis scores in osteosarcoma. Ther Drug Monit 33:711–718. https://doi.org/10.1097/FTD.0b013e31823615e1

    Article  CAS  PubMed  Google Scholar 

  53. Joerger M, Ferreri AJ, Krähenbühl S, Schellens JH, Cerny T, Zucca E, Huitema ADR (2012) Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate. Br J Clin Pharmacol 73:240–247. https://doi.org/10.1111/j.1365-2125.2011.04084.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang W, Zhang Q, Tian X, Zhao H, Lu W, Zhen J, Niu X (2015) Population pharmacokinetics of high-dose methotrexate after intravenous administration in Chinese osteosarcoma patients from a single institution. Chin Med J (Engl) 128:111–118. https://doi.org/10.4103/0366-6999.147829

    Article  CAS  PubMed  Google Scholar 

  55. Kawakatsu S, Nikanjam M, Lin M, Le S, Saunders I, Kuo DJ, Capparelli EV (2019) Population pharmacokinetic analysis of high-dose methotrexate in pediatric and adult oncology patients. Cancer Chemother Pharmacol 84:1339–1348. https://doi.org/10.1007/s00280-019-03966-4

    Article  CAS  PubMed  Google Scholar 

  56. Schulte RR, Choi L, Utreja N, Van Driest SL, Stein CM, Ho RH (2021) Effect of SLCO1B1 polymorphisms on high-dose methotrexate clearance in children and young adults with leukemia and lymphoblastic lymphoma. Clin Transl Sci 14:343–353. https://doi.org/10.1111/cts.12879

    Article  CAS  PubMed  Google Scholar 

  57. Godfrey C, Sweeney K, Miller K, Hamilton R, Kremer J (1998) The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol 46:369–376. https://doi.org/10.1046/j.1365-2125.1998.t01-1-00790.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Batey MA, Wright JG, Azzabi A, Newell DR, Lind MJ, Calvert AH, Boddy AV (2002) Population pharmacokinetics of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Eur J Cancer 38:1081–1089. https://doi.org/10.1016/s0959-8049(02)00024-2

    Article  CAS  PubMed  Google Scholar 

  59. Yukawa E, Mori S, Ueda K, Nakada Y (2007) Population pharmacokinetic investigation of low-dose methotrexate in rheumatoid arthritics Japanese patients. J Clin Pharm Ther 32:573–578. https://doi.org/10.1111/j.1365-2710.2007.00859.x

    Article  CAS  PubMed  Google Scholar 

  60. Nagulu M, Kiran VU, Nalini Y, Reddy YN, Krishna DR (2010) Population pharmacokinetics of methotrexate in Indian cancer patients. Asian Pac J Cancer Prev 11:403–407

    PubMed  Google Scholar 

  61. Kim IW, Yun HY, Choi B, Han N, Park SY, Lee ES, Oh JM (2012) ABCB1 C3435T genetic polymorphism on population pharmacokinetics of methotrexate after hematopoietic stem cell transplantation in Korean patients: a prospective analysis. Clin Ther 34:1816–1826. https://doi.org/10.1016/j.clinthera.2012.06.022

    Article  CAS  PubMed  Google Scholar 

  62. Wang Z, Zhang N, Chen C, Chen S, Xu J, Zhou Y, Zhao X, Cui Y (2019) Influence of the OATP polymorphism on the population pharmacokinetics of methotrexate in Chinese patients. Curr Drug Metab 20:592–600. https://doi.org/10.2174/1389200220666190701094756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Crews KR, Liu T, Rodriguez-Galindo C, Tan M, Meyer WH, Panetta JC, Link MP, Daw NC (2004) High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma. Cancer 100:1724–1733. https://doi.org/10.1002/cncr.20152

    Article  CAS  PubMed  Google Scholar 

  64. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH (1998) Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 338:499–505. https://doi.org/10.1056/NEJM199802193380803. (PubMed: 9468466)

    Article  CAS  PubMed  Google Scholar 

  65. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NHG (2009) Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 24:67–76. https://doi.org/10.1007/s00467-008-0997-5

    Article  PubMed  Google Scholar 

  66. Donelli MG, Zucchetti M, Robatto A, Perlangeli V, D’Incalci M, Masera G, Rossi MR (1995) Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. Med Pediatr Oncol 24:154–159. https://doi.org/10.1002/mpo.2950240303

    Article  CAS  PubMed  Google Scholar 

  67. Ceriotti F, Boyd JC, Klein G, Henny J, Queraltó J, Kairisto V, Panteghini M, Committee IFCC, on Reference Intervals and Decision Limits (C-RIDL), (2008) Reference intervals for serum creatinine concentrations: assessment of available data for global application. Clin Chem 54:559–566. https://doi.org/10.1373/clinchem.2007.099648

    Article  PubMed  Google Scholar 

  68. den Boer E, de Rotte MC, Pluijm SM, Heil SG, Hazes JM, de Jonge R (2014) Determinants of erythrocyte methotrexate polyglutamate levels in rheumatoid arthritis. J Rheumatol 41:2167–2178. https://doi.org/10.3899/jrheum.131290

    Article  CAS  Google Scholar 

  69. Stamp LK, O’Donnell JL, Chapman PT, Zhang M, Frampton C, James J, Barclay ML (2009) Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long-term methotrexate treatment. Arthritis Rheum 60:2248–2256. https://doi.org/10.1002/art.24653

    Article  CAS  PubMed  Google Scholar 

  70. Foissac F, Bouazza N, Valade E, De Sousa MM, Fauchet F, Benaboud S, Hirt D, Tréluyer JM, Urien S (2015) Prediction of drug clearance in children. J Clin Pharmacol 55:739–747. https://doi.org/10.1002/jcph.488

    Article  PubMed  Google Scholar 

  71. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ (2000) Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 18:547–561. https://doi.org/10.1200/JCO.2000.18.3.547

    Article  CAS  PubMed  Google Scholar 

  72. Fabre G, Fabre I, Matherly LH, Cano JP, Goldman ID (1984) Synthesis and properties of 7-hydroxymethotrexate polyglutamyl derivatives in Ehrlich ascites tumor cells in vitro. J Biol Chem 259:5066–5072. https://doi.org/10.1016/S0021-9258(17)42956-5

    Article  CAS  PubMed  Google Scholar 

  73. Dupuis C, Mercier C, Yang C, Monjanel-Mouterde S, Ciccolini J, Fanciullino R, Pourroy B, Deville JL, Duffaud F, Bagarry-Liegey D, Durand A, Iliadis A, Favre R (2008) High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy. Anticancer Drugs 19:267–273. https://doi.org/10.1097/cad.0b013e3282f21376

    Article  CAS  PubMed  Google Scholar 

  74. Relling MV, Fairclough D, Ayers D, Crom WR, Rodman JH, Pui CH, Evans WE (1994) Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol 12:1667–1672. https://doi.org/10.1200/JCO.1994.12.8.1667

    Article  CAS  PubMed  Google Scholar 

  75. Hendel J, Nyfors A (1984) Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol 26:121–124. https://doi.org/10.1007/BF00546719

    Article  CAS  PubMed  Google Scholar 

  76. Mikkelsen TS, Thorn CF, Yang JJ, Ulrich CM, French D, Zaza G, Dunnenberger HM, Marsh S, McLeod HL, Giacomini K, Becker ML, Gaedigk R, Leeder JS, Kager L, Relling MV, Evans W, Klein TE, Altman RB (2011) PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics 21:679–686. https://doi.org/10.1097/FPC.0b013e328343dd93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Borsi JD, Moe PJ (1987) A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 to 33.6 g/m2 in children with acute lymphoblastic leukemia. Cancer 60:5–13

Download references

Acknowledgements

We extend our heartfelt gratitude to the following individuals and institutions for their invaluable contributions: Dr. Daniel Gonzalez from the UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, USA; Dr. Tai Ning Lam from the Lo Kwee-Seong Integrated Biomedical Sciences Building, The Chinese University of Hong Kong, Hong Kong; Dr. Tetsuichiro Isono and Dr. Shin-ya Morita from the Department of Pharmacy, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan; Dr. Zhigang Zhao from the Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China; and Dr. Joseph F. Standing from the Department of Pharmacy, Great Ormond Street Hospital for Children, United Kingdom for providing the NONMEM control stream from their previously published population pharmacokinetic models. We would also like to thank Editage (www.editage.cn) for English language editing.

Funding

This study was supported by the Shanghai Changhai Hospital Youth Start-up Fund Project, “Study on the dose–response relationship mechanism of Wuzhi capsule increasing tacrolimus concentration based on population pharmacokinetic model” (grant number: 2020QNB11), and the Special youth cultivation project for basic medical research of Changhai Hospital, “Establishment of cyclosporine PK/PD model in patients with RIF based on trophoblastic organs and its pharmacodynamic mechanism” (grant number: 2021JCQN19).

Author information

Author notes

  1. Yunyun Yang, Zhengyue Liu, and Jingxia Chen equally contributed to this study.

Authors and Affiliations

  1. Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Navy Medical University, 168 Changhai Rd, Shanghai, 200433, China

    Yunyun Yang, Zhengyue Liu, Jingxia Chen, Xuebin Wang & Zhuo Wang

  2. Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai, 200030, China

    Zheng Jiao

Authors
  1. Yunyun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhengyue Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jingxia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuebin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhuo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YYY, ZW, and ZJ designed the review and planned the work that led to the manuscript. ZL and CW performed the literature search and data analysis. YYY, ZW, and ZJ drafted and revised the manuscript. All authors approved the final version of this manuscript.

Corresponding authors

Correspondence to Zheng Jiao or Zhuo Wang.

Ethics declarations

Ethics approval

No ethical approval is required/exemption granted.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 23 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Liu, Z., Chen, J. et al. Factors influencing methotrexate pharmacokinetics highlight the need for individualized dose adjustment: a systematic review. Eur J Clin Pharmacol 80, 11–37 (2024). https://doi.org/10.1007/s00228-023-03579-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-023-03579-0

Keywords

Search

Navigation