Skip to main content
SpringerLink
Log in

Pharmacokinetics of tablet and liquid formulations of oral 6-mercaptopurine in children with acute lymphoblastic leukemia

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL.

Methods

Pharmacokinetics of 50 mg 6MP tablet (Puri-Nethol®) and 20 mg/ml 6MP liquid suspension (Xaluprine®) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12 h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and terminal half-life (T½).

Results

Liquid 6MP formulation resulted in a 26% lower AUC (p = 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for Cmax,Tmax and T½ (p = 0.28, p = 0.09, p = 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet.

Conclusion

Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL.

The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13.

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. 1a
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Toft N, Birgens H, Abrahamsson J, Griskevicius L, Hallbook H, Heyman M, Klausen TW, Jonsson OG, Palk K, Pruunsild K, Quist-Paulsen P, Vaitkeviciene G, Vettenranta K, Asberg A, Frandsen TL, Marquart HV, Madsen HO, Noren-Nystrom U, Schmiegelow K (2018) Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia. Leukemia 32(3):606–615. https://doi.org/10.1038/leu.2017.265

    Article  CAS  PubMed  Google Scholar 

  2. Hunger SP, Mullighan CG (2015) Acute lymphoblastic leukemia in children. N Engl J Med 373(16):1541–1552. https://doi.org/10.1056/NEJMra1400972

    Article  CAS  PubMed  Google Scholar 

  3. Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, Egeler RM, Hoogerbrugge P, Kaspers G, Van der Schoot E, De Haas V, Van Dongen J (2016) Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol 34(22):2591–2601. https://doi.org/10.1200/jco.2015.64.6364

    Article  PubMed  Google Scholar 

  4. Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM (2012) Acute leukemia incidence and patient survival among children and adults in the United States, 2001–2007. Blood 119(1):34–43. https://doi.org/10.1182/blood-2011-04-347872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J (2014) Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol 36(7):503–517. https://doi.org/10.1097/mph.0000000000000206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Toyoda Y, Manabe A, Tsuchida M, Hanada R, Ikuta K, Okimoto Y, Ohara A, Ohkawa Y, Mori T, Ishimoto K, Sato T, Kaneko T, Maeda M, Koike K, Shitara T, Hoshi Y, Hosoya R, Tsunematsu Y, Bessho F, Nakazawa S, Saito T (2000) Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood. J Clin Oncol 18(7):1508–1516. https://doi.org/10.1200/jco.2000.18.7.1508

    Article  CAS  PubMed  Google Scholar 

  7. Riehm H, Gadner H, Henze G, Kornhuber B, Lampert F, Niethammer D, Reiter A, Schellong G (1990) Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematol Blood Transfus 33:439–450. https://doi.org/10.1007/978-3-642-74643-7_81

    Article  CAS  PubMed  Google Scholar 

  8. Nielsen SN, Grell K, Nersting J, Abrahamsson J, Lund B, Kanerva J, Jonsson OG, Vaitkeviciene G, Pruunsild K, Hjalgrim LL, Schmiegelow K (2017) DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial. Lancet Oncol 18(4):515–524. https://doi.org/10.1016/s1470-2045(17)30154-7

    Article  CAS  PubMed  Google Scholar 

  9. Bhatia S, Landier W, Shangguan M, Hageman L, Schaible AN, Carter AR, Hanby CL, Leisenring W, Yasui Y, Kornegay NM, Mascarenhas L, Ritchey AK, Casillas JN, Dickens DS, Meza J, Carroll WL, Relling MV, Wong FL (2012) Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group. J Clin Oncol 30(17):2094–2101. https://doi.org/10.1200/JCO.2011.38.9924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kato M, Ishimaru S, Seki M, Yoshida K, Shiraishi Y, Chiba K, Kakiuchi N, Sato Y, Ueno H, Tanaka H, Inukai T, Tomizawa D, Hasegawa D, Osumi T, Arakawa Y, Aoki T, Okuya M, Kaizu K, Kato K, Taneyama Y, Goto H, Taki T, Takagi M, Sanada M, Koh K, Takita J, Miyano S, Ogawa S, Ohara A, Tsuchida M, Manabe A (2017) Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children. Leukemia 31(3):580–584. https://doi.org/10.1038/leu.2016.274

    Article  CAS  PubMed  Google Scholar 

  11. Zimm S, Collins JM, Riccardi R, O'Neill D, Narang PK, Chabner B, Poplack DG (1983) Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 308(17):1005–1009. https://doi.org/10.1056/NEJM198304283081705

    Article  CAS  PubMed  Google Scholar 

  12. Balis FM, Holcenberg JS, Poplack DG, Ge J, Sather HN, Murphy RF, Ames MM, Waskerwitz MJ, Tubergen DG, Zimm S, Gilchrist GS, Bleyer WA (1998) Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study. Blood 92(10):3569–3577

    Article  CAS  Google Scholar 

  13. Lennard L, Keen D, Lilleyman JS (1986) Oral 6-mercaptopurine in childhood leukemia: parent drug pharmacokinetics and active metabolite concentrations. Clin Pharmacol Ther 40(3):287–292. https://doi.org/10.1038/clpt.1986.178

    Article  CAS  PubMed  Google Scholar 

  14. Sulh H, Koren G, Whalen C, Soldin S, Zipursky A, Greenberg M (1986) Pharmacokinetic determinants of 6-mercaptopurine myelotoxicity and therapeutic failure in children with acute lymphoblastic leukemia. Clin Pharmacol Ther 40(6):604–609. https://doi.org/10.1038/clpt.1986.233

    Article  CAS  PubMed  Google Scholar 

  15. Breitkreutz J, Buckham J, Fischer R, Pöstges R, Boos J (2007) Comparative in vitro studies on different 6-mercaptopurine formulations for use in children. Paediatr Perinatal Drug Ther 8:1

    Article  Google Scholar 

  16. Mulla H, Leary A, White P, Pandya HC (2012) A step toward more accurate dosing for mercaptopurine in childhood acute lymphoblastic leukemia. J Clin Pharmacol 52(10):1610–1613. https://doi.org/10.1177/0091270011423663

    Article  CAS  PubMed  Google Scholar 

  17. Frandsen TL, Heyman M, Abrahamsson J, Vettenranta K, Asberg A, Vaitkeviciene G, Pruunsild K, Toft N, Birgens H, Hallbook H, Quist-Paulsen P, Griskevicius L, Helt L, Hansen BV, Schmiegelow K (2014) Complying with the European Clinical Trials directive while surviving the administrative pressure—an alternative approach to toxicity registration in a cancer trial. Eur J Cancer 50(2):251–259. https://doi.org/10.1016/j.ejca.2013.09.027

    Article  PubMed  Google Scholar 

  18. Toft N, Birgens H, Abrahamsson J, Bernell P, Griskevicius L, Hallbook H, Heyman M, Holm MS, Hulegardh E, Klausen TW, Marquart HV, Jonsson OG, Nielsen OJ, Quist-Paulsen P, Taskinen M, Vaitkeviciene G, Vettenranta K, Asberg A, Schmiegelow K (2013) Risk group assignment differs for children and adults 1–45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol. Eur J Haematol 90(5):404–412. https://doi.org/10.1111/ejh.12097

    Article  PubMed  Google Scholar 

  19. Report WT (2016) WHO Guidance for organizations performing in vivo bioequivalence studies. Series No. 996, Annex 9

  20. Arico M, Baruchel A, Bertrand Y, Biondi A, Conter V, Eden T, Gadner H, Gaynon P, Horibe K, Hunger SP, Janka-Schaub G, Masera G, Nachman J, Pieters R, Schrappe M, SchmiegelowValsecchi KMG, Pui CH (2005) The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29–30, 2005. Leukemia 19(7):1145–1152. https://doi.org/10.1038/sj.leu.2403783

    Article  CAS  PubMed  Google Scholar 

  21. Schmiegelow K, Nersting J, Nielsen SN, Heyman M, Wesenberg F, Kristinsson J, Vettenranta K, Schroeder H, Weinshilboum R, Jensen KL, Grell K, Rosthoej S (2016) Maintenance therapy of childhood acute lymphoblastic leukemia revisited—should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts? Pediatr Blood Cancer 63(12):2104–2111. https://doi.org/10.1002/pbc.26139

    Article  CAS  PubMed  Google Scholar 

  22. Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, Giesbrecht E, Soldin S, Greenberg M (1990) Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med 323(1):17–21. https://doi.org/10.1056/NEJM199007053230104

    Article  CAS  PubMed  Google Scholar 

  23. Karran P, Attard N (2008) Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer 8(1):24–36. https://doi.org/10.1038/nrc2292

    Article  CAS  PubMed  Google Scholar 

  24. Diouf B, Cheng Q, Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H, Chen S, Thierfelder WE, Mullighan CG, Downing JR, Hsieh P, Pui CH, Relling MV, Evans WE (2011) Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nat Med 17(10):1298–1303. https://doi.org/10.1038/nm.2430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Waters TR, Swann PF (1997) Cytotoxic mechanism of 6-thioguanine: hMutSalpha, the human mismatch binding heterodimer, binds to DNA containing S6-methylthioguanine. Biochemistry 36(9):2501–2506. https://doi.org/10.1021/bi9621573

    Article  CAS  PubMed  Google Scholar 

  26. Swann PF, Waters TR, Moulton DC, Xu YZ, Zheng Q, Edwards M, Mace R (1996) Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273(5278):1109–1111. https://doi.org/10.1126/science.273.5278.1109

    Article  CAS  PubMed  Google Scholar 

  27. Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J, Makipernaa A, Rosthoj S, Szumlanski C, Sorensen TM, Weinshilboum R (2003) Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol 21(7):1332–1339. https://doi.org/10.1200/jco.2003.04.039

    Article  CAS  PubMed  Google Scholar 

  28. Tolbert JA, Bai S, Abdel-Rahman SM, August KJ, Weir SJ, Kearns GL, Neville KA (2017) Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 64:8. https://doi.org/10.1002/pbc.26465

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the dedicated staff at the laboratory of Pediatric Oncology, Bonkolab, Copenhagen for their valuable work.

Funding

Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, The Capital Region of Denmark, and The University Hospital Rigshospitalet.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark

    Rikke Hebo Larsen, Lisa Lyngsie Hjalgrim, Kathrine Grell, Line Gerner Pedersen, Emilie Damgaard Brünner, Bodil Als-Nielsen, Kjeld Schmiegelow & Jacob Nersting

  2. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark

    Kathrine Grell

  3. Discovery and Development PKPD, Novo Nordisk, Copenhagen, Denmark

    Kim Kristensen

  4. Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark

    Kjeld Schmiegelow

Authors
  1. Rikke Hebo Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa Lyngsie Hjalgrim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathrine Grell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kim Kristensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Line Gerner Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emilie Damgaard Brünner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bodil Als-Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kjeld Schmiegelow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jacob Nersting
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RHL coordinated the study, compiled data, performed statistical analysis, and drafted the manuscript. EB drafted the study protocol and obtained relevant permissions. LP compiled data. KK did the pharmacokinetic analysis. KG supervised the statistical analysis. JN performed analyses of plasma 6MP and supervised the study. LH supervised the study. BAN supervised the study. KS initiated and supervised the study and had responsibility for the final submission for publication. All authors approved the final manuscript.

Corresponding author

Correspondence to Jacob Nersting.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The 6MP pharmacokinetic study was approved by the Ethical Committee of the Capital Region of Denmark (H-3-2013-074). The study was performed in accordance with the 1964 Helsinki Declaration and its later amendments and approved by Ethical Committee of the Capital Region of Denmark (H-3-2013-074).

Consent to participate

Written informed consent was obtained from all participants or legal guardians.

Consent for publication

All authors approved the final manuscript.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Larsen, R.H., Hjalgrim, L.L., Grell, K. et al. Pharmacokinetics of tablet and liquid formulations of oral 6-mercaptopurine in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 86, 25–32 (2020). https://doi.org/10.1007/s00280-020-04097-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-020-04097-x

Keywords

Search

Navigation