Advertisement

Therapeutic drug monitoring of imatinib in patients with gastrointestinal stromal tumours – Results from daily clinical practice

  • Author Footnotes
    1 These authors contributed equally.
    Nikki S. IJzerman
    Correspondence
    Corresponding author: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands

    Erasmus MC – Cancer Institute, Department of Medical Oncology, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally.
    Stefanie L. Groenland
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
    Search for articles by this author
  • Anne Miek Koenen
    Affiliations
    Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
    Search for articles by this author
  • Martijn Kerst
    Affiliations
    Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
    Search for articles by this author
  • Winette T.A. van der Graaf
    Affiliations
    Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
    Search for articles by this author
  • Hilde Rosing
    Affiliations
    Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
    Search for articles by this author
  • Jos H. Beijnen
    Affiliations
    Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands

    Department of Pharmaceutical Sciences, Utrecht University, Heidelberglaan 8, 3584 CS, Utrecht, the Netherlands
    Search for articles by this author
  • Alwin D.R. Huitema
    Affiliations
    Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands

    Department of Clinical Pharmacy, University Medical Center, Utrecht University, Heidelberglaan 8, 3584 CS, Utrecht, the Netherlands
    Search for articles by this author
  • Neeltje Steeghs
    Affiliations
    Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally.

      Highlights

      • Seventy-five percent of patients had an imatinib exposure below the minimum plasma concentration threshold of 1100 ng/mL.
      • In 62% of these patients, the imatinib dose was increased to either 600 mg or 800 mg.
      • This PK-guided dose increase was successful in 63% of patients.
      • Therapeutic drug monitoring of imatinib is feasible in clinical practice.

      Abstract

      Aim

      Higher imatinib exposure is correlated with longer time to progression, while the variability in exposure is high. This provides a strong rationale for therapeutic drug monitoring, which has therefore been implemented in routine clinical practice in our institute. The aim of this study is to evaluate whether pharmacokinetically (PK)-guided dose increases are feasible in daily clinical practice and result in an improved exposure (Cmin≥1100 ng/mL) and longer progression-free survival (PFS).

      Methods

      This retrospective study included all patients with a gastrointestinal stromal tumour (GIST) in the Netherlands Cancer Institute who started imatinib treatment at a dose of 400 mg and of whom PK plasma samples were available. Of these patients, minimum plasma concentrations (Cmin) of imatinib, frequency and successfulness of PK-guided dose increases and PFS in the palliative treatment setting were analysed.

      Results

      In total, 169 consecutive patients were included, of whom 1402 PK samples were collected. In 126 patients (75%), Cmin was below the efficacy threshold of 1100 ng/mL. In 78 of these patients (62%), a PK-guided dose increase was performed, which was successful in 49 patients (63%). PFS was similar in patients with and without imatinib dose increase. However, due to the small number of patients with progressive disease, no definite conclusions on the effect on PFS could yet be drawn.

      Conclusion

      This is the largest cohort evaluating PK-guided dose increases of imatinib in patients with GIST in routine clinical practice and demonstrating its feasibility. PK-guided dose increases should be applied to optimise exposure in the significant subset of patients with a low Cmin.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Güller U.
        • Tarantino I.
        • Cerny T.
        • Schmied B.M.
        • Warschkow R.
        Population-based SEER trend analysis of overall and cancer-specific survival in 5138 patients with gastrointestinal stromal tumor.
        BMC Canc. 2015; 15: 557
        • Demetri G.D.
        • Wang Y.
        • Wehrle E.
        • Racine A.
        • Nikolova Z.
        • Blanke C.D.
        • et al.
        Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors.
        J Clin Oncol. 2009; 27: 3141-3147
        • Guilhot F.
        • Hughes T.P.
        • Cortes J.
        • Druker B.J.
        • Baccarani M.
        • Gathmann I.
        • et al.
        Plasma exposure of imatinib and its correlation with clinical response in the tyrosine kinase inhibitor optimization and selectivity trial.
        Haematologica. 2012; 97: 731-738
        • Larson R.A.
        • Druker B.J.
        • Guilhot F.
        • O'Brien S.G.
        • Riviere G.J.
        • Krahnke T.
        • et al.
        Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study.
        Blood. 2008; 111: 4022-4028
        • Picard S.
        • Titier K.
        • Etienne G.
        • Teilhet E.
        • Ducint D.
        • Bernard M.A.
        • et al.
        Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia.
        Blood. 2007; 109: 3496-3499
        • Yoo C.
        • Ryu M.H.
        • Ryoo B.Y.
        • Beck M.Y.
        • Kang Y.K.
        Efficacy, safety, and pharmacokinetics of imatinib dose escalation to 800 mg/day in patients with advanced gastrointestinal stromal tumors.
        Invest N Drugs. 2013; 31: 1367-1374
        • Bouchet S.
        • Poulette S.
        • Titier K.
        • Moore N.
        • Lassalle R.
        • Abouelfath A.
        • et al.
        Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting.
        Eur J Canc. 2016; 57: 31-38
        • Eechoute K.
        • Fransson M.N.
        • Reyners A.K.
        • de Jong F.A.
        • Sparreboom A.
        • van der Graaf W.T.
        • et al.
        A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients.
        Clin Canc Res. 2012; 18: 5780-5787
        • Farag S.
        • Verheijen R.B.
        • Martijn Kerst J.
        • Cats A.
        • Huitema A.D.
        • Steeghs N.
        Imatinib pharmacokinetics in a large observational cohort of gastrointestinal stromal tumour patients.
        Clin Pharmacokinet. 2017; 56: 287-292
        • Lankheet N.A.G.
        • Desar I.M.E.
        • Mulder S.F.
        • Burger D.M.
        • Kweekel D.M.
        • van Herpen C.M.L.
        • et al.
        Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib.
        Br J Clin Pharmacol. 2017; 83: 2195-2204
        • Lankheet N.A.
        • Knapen L.M.
        • Schellens J.H.
        • Beijnen J.H.
        • Steeghs N.
        • Huitema A.D.
        Plasma concentrations of tyrosine kinase inhibitors imatinib, erlotinib, and sunitinib in routine clinical outpatient cancer care.
        Ther Drug Monit. 2014; 36: 326-334
        • Zuidema S.
        • Desar I.M.E.
        • van Erp N.P.
        • Kievit W.
        Optimizing the dose in patients treated with imatinib as first line treatment for gastrointestinal stromal tumors: a cost-effectiveness study.
        Br J Clin Pharmacol. 2019; 85: 1994-2001
        • Wang S.Y.
        • Wu C.E.
        • Lai C.C.
        • Chen J.S.
        • Tsai C.Y.
        • Cheng C.T.
        • et al.
        Prospective evaluation of neoadjuvant imatinib use in locally advanced gastrointestinal stromal tumors: emphasis on the optimal duration of neoadjuvant imatinib use, safety, and oncological outcome.
        Cancers (Basel). 2019; 11
        • Rutkowski P.
        • Gronchi A.
        • Hohenberger P.
        • Bonvalot S.
        • Schöffski P.
        • Bauer S.
        • et al.
        Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG experience.
        Ann Surg Oncol. 2013; 20: 2937-2943
        • Joensuu H.
        • Eriksson M.
        • Sundby Hall K.
        • Hartmann J.T.
        • Pink D.
        • Schütte J.
        • et al.
        One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.
        JAMA. 2012; 307: 1265-1272
        • Casali P.G.
        • Abecassis N.
        • Aro H.T.
        • Bauer S.
        • Biagini R.
        • Bielack S.
        • et al.
        Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2018; 29: iv267
        • Herbrink M.
        • de Vries N.
        • Rosing H.
        • Huitema A.D.
        • Nuijen B.
        • Schellens J.H.
        • et al.
        Quantification of 11 therapeutic kinase inhibitors in human plasma for therapeutic drug monitoring using liquid chromatography coupled with tandem mass spectrometry.
        Ther Drug Monit. 2016; 38: 649-656
        • Wang Y.
        • Chia Y.L.
        • Nedelman J.
        • Schran H.
        • Mahon F.X.
        • Molimard M.
        A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times.
        Ther Drug Monit. 2009; 31: 579-584
        • (EMA) EMA
        Summary of product characteristics glivec (imatinib).
        • Janssen D.J.M.
        • Dorlo D.T.P.C.
        • Beijnen P.D.J.H.
        • Huitema P.D.A.D.
        Evaluation of extrapolation methods to predict trough concentrations to guide therapeutic drug monitoring of oral anticancer drugs.
        Ther Drug Monit. 2020; https://doi.org/10.1097/FTD.0000000000000767
        • Miettinen M.
        • Lasota J.
        Gastrointestinal stromal tumors: pathology and prognosis at different sites.
        Semin Diagn Pathol. 2006; 23: 70-83
        • Casali P.G.
        • Zalcberg J.
        • Le Cesne A.
        • Reichardt P.
        • Blay J.Y.
        • Lindner L.H.
        • et al.
        Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European organisation for research and treatment of cancer, Italian sarcoma group, and australasian gastrointestinal trials group intergroup phase III randomized trial on imatinib at two dose levels.
        J Clin Oncol. 2017; 35: 1713-1720
        • Widmer N.
        • Decosterd L.A.
        • Csajka C.
        • Leyvraz S.
        • Duchosal M.A.
        • Rosselet A.
        • et al.
        Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein.
        Br J Clin Pharmacol. 2006; 62: 97-112
        • Gotta V.
        • Widmer N.
        • Decosterd L.A.
        • Chalandon Y.
        • Heim D.
        • Gregor M.
        • et al.
        Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.
        Canc Chemother Pharmacol. 2014; 74: 1307-1319