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  • Pharmacokinetics and Pharmacodynamics of

    Tyrosine Kinase Inhibitors

    Jacqueline SL Kloth

    Pharmacokinetics and Pharm

    acodynamics of Tyrosine Kinase Inhibitors

    Jacqueline SL Kloth

  • Pharmacokinetics and Pharmacodynamics of

    Tyrosine Kinase InhibitorsFarmacokinetiek en farmacodynamiek

    van tyrosine kinase remmers

    Jacqueline S.L. Kloth

  • ColofonKloth, J.S.L.Pharmacokinetics and Pharmacodynamics of Tyrosine Kinase InhibitorsISBN: 978-94-6182-572-8

    Lay-out and cover Design: Roderick van KlinkPrinted by: Off pageCopyright J.S.L. Kloth 2015, Rotterdam, The Netherlands

    All rights reserved. No part of this thesis may be reproduced, stored in a retrival system of any nature, or transmitted in any form or means, without written permission of the author, or when appropriate, of the publishers of the publications.The printing of this thesis was sponsored by Teva Nederland B.V., Waters Chromatography B.V., ChipSoft B.V., Pfizer B.V. and Boehringer Ingelheim B.V.

  • Pharmacokinetics and Pharmacodynamics of Tyrosine Kinase Inhibitors

    Farmacokinetiek en farmacodynamiek van tyrosine kinase remmers

    Proefschrift

    ter verkrijging van de graad van doctor aan deErasmus Universiteit Rotterdam

    op gezag van de rector magnificus

    Prof.dr. H.A.P. Pols

    en volgens besluit van het College voor Promoties.

    De openbare verdediging zal plaatsvinden op

    woensdag 1 juli 2015 om 11.30 uur

    door

    Jacqueline S.L. Kloth

    geboren te Dordrecht

  • PromoTIecommIssIePromotor Prof.dr. A.H.J. Mathijssen

    Overige leden Prof.dr. T. van Gelder Prof.dr. H.J. Guchelaar Prof.dr. W.T.A. van der Graaf

    Copromotor dr. E.A.C. Wiemer

  • Het komt altijd goedC. van Noord

  • coNTeNTsChapter 1 General introduction

    Part I: Pharmacokinetic approach towards improved sunitinib treatmentChapter 2 Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: the ClearSun study Chapter 3 Pharmacokinetically-guided sunitinib dosing: A feasibility study in patients with advanced solid tumours Chapter 4 Relationship between sunitinib pharmacokinetics and administration time: preclinical and clinical evidence Part II: Pharmacodynamic aspects of treatment with tyrosine kinase inhibitorsChapter 5 Genetic polymorphisms as predictive biomarker for survival in patients with gastro-intestinal stromal tumours treated with sunitinib Chapter 6 Genetic polymorphisms in angiogenesis related genes are predictive for survival of patients with advanced gastrointestinal stromal tumors treated with imatinib

    Chapter 7 Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors Chapter 8 Macrocytosis as a predictive marker for survival in the treatment with tyrosine kinase inhibitors Chapter 9 Summary

    Appendices Nederlandse samenvatting Curriculum Vitae Publications PhD portfolio Dankwoord

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  • chapter 1General introduction

  • 10

    cANcerCancer is the second most common cause of death worldwide after cardiovascular diseases, responsible for an estimated 8.4 million deaths in 2012 and its incidence is still increasing.1 Through the introduction of many chemotherapeutic agents and hormone treatments in the last decades, treatment options for patients with advanced forms of cancer have improved. Mortality rates have decreased and in some cases cancer is now changing to become a chronic disease. More recent, increased insight in cancer cell biology has led to further improvement in anti-cancer treatment. Much attention has been focused on tyrosine kinases that comprise essential elements of cellular signalling cascades which control proliferation, cell survival and cell death. In cancer, tyrosine kinases can be found activated by mutations, thereby contributing to malignant transformation, tumour growth and metastasis.

    TYrosINe KINAse INHIBITors Targeted therapies, especially tyrosine kinase inhibitors (TKIs), have largely contributed to the recent improvement in anti-cancer treatment. TKIs usually act by competing with adenosine 5- triphosphate (ATP) for the intracellular ATP binding site of one or more tyrosine kinases.2 ATP displacement by TKI binding results in inhibition of several processes which are necessary for tumour growth, such as angiogenesis, cell proliferation and cell migration (type I inhibitors).3 More recently, TKIs have been developed which are non-ATP competitive inhibitors (type II and type III inhibitors). Currently, 17 TKIs are available for the treatment of a broad variety of cancer types, with approval by both the US Food and Drug Administration and European Medicines Agency (Table 1).4

    TKIs are oral drugs which are usually administered on a daily base. In the year 2000, imatinib was the first TKI that became available on the market for the treatment of chronic myeloid leukaemia (CML). By blocking BCR-ABL, a fusion gene frequently mutated in patients with CML, imatinib is able to inhibit myeloid cell growth.5, 6 In a later stage, imatinib was also found to be effective in the treatment of gastrointestinal stromal tumours (GIST), by inhibition of c-KIT and PDGFR-.7 c-KIT is mutated in over 90% of GISTs and PDGFR in most c-KIT negative GIST.8-10 Since the introduction of imatinib, overall survival of patients with metastatic GIST has improved drastically. Earlier, only 15% of patients with advanced GIST were still alive 2 years after diagnosis. Nowadays, progression free survival on imatinib treatment is 2-2.5 years, and 10% of patients with advanced GIST has been treated with imatinib for more than 10 years without progression of the disease.7, 11, 12

    The introduction of sunitinib, a multi-target tyrosine kinase inhibitor of c-KIT, PDGFR-, PDGFR-, VEGF receptors 1, 2 and 3, CSF-1R and FLT3,12-14 as a second line treatment for imatinib resistant or intolerant GIST further increased progression free survival from 6 weeks to 27 weeks.15 And since 2014, even a third-line TKI (regorafenib) is approved for GIST, further improving survival.16 Besides the

    Chapter 1

    1

  • 11

    indication as second line for GIST, sunitinib has proven efficacy in the treatment of advanced renal cell carcinoma and neuro-endocrine tumours of the pancreas.17, 18 These are just some examples of how TKIs have improved anti-cancer therapies and have been implemented in todays anti-cancer treatment.

    Table 1 Tyrosine kinase inhibitorsTKI Inhibited kinases Indication

    Afatinib EGFR EGFR+ NSCLC19

    Axitinib VEGFR-1, VEGFR-2, VEGFR-3 Renal cell cancer20

    Bosutinib SRC, ABL Ph+ CML21

    Cabozantinib MET, VEGFR-2, RET Medullary thyroid carcinoma22

    Crizotinib ALK, HGFR, RON, ROS1 ALK+ NSCLC23

    Dasatinib BCR-ABL, c-KIT, PDGFR-, SRC, EPHA-2 Ph+ CML, Ph+ ALL24

    Erlotinib EGFR EGFR+ NSCLC, metastatic pancreas carcinoma25

    Gefitinib EGFR EGFR+ NSCLC26

    Imatinib BCR-ABL, c-KIT, PDGFR-, PDGFR-, DDR-1, DDR-2, CSF-1RGIST, CML, ALL, dermatofibrosarcoma protuberans27

    Lapatinib HER2, EGFR HER2+ Breast cancer28

    Nilotinib BCR-ABL, PDGFR-, PDGFR-, c-KIT, CSF-1R, DDR Ph+ CML29

    Pazopanib VEGFR-1, VEGFR-2, VEGFR-3, c-KIT, PDGFR-, PDGFR-, FGFR-1, FGFR-3, LTK, LCK, c-FMS Renal cell cancer, soft tissue sarcoma30

    Regorafenib VEGFR-1, VEGFR-2, VEGFR-3, TIE2, c-KIT, RET, RAF-1, BRAF, PDGFR, FGFR colorectal , GIST31

    Sorafenib VEGFR-2, VEGFR-3, PDGFR-, C-RAF, B-RAF, FLT3, c-KitRenal cell cancer, HCC, non-medullary thyroid carcinoma32

    Sunitinib VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-, PDGFR-, c-KIT, RET, FLT3, CSF-1R Renal cell cancer, GIST, p-NET33

    Vandetanib EGFR, VEGFR-2, RET Medullary thyroid carcinoma34

    Vemurafenib BRAF Braf V600E+ melanoma35

    PersoNALIZeD meDIcINeAlthough there is (at least) 30-35% inter-patient variability in both pharmacokinetics and pharmacodynamics for most TKIs, these drugs are still prescribed in a fixed dosing schedule. Side effects are common in TKI treatment and not occasionally patients require dose reductions or discontinuations due to adverse effects. Furthermore, not all patients respond similarly to TKI treatment. A small proportion of patients suffer from initial resistance to a drug, and regardless of which TKI is used for which indication, eventually all patients become drug resistant resulting in

    General introduction

    1

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    tumour growth. These observations suggest that personalized medicine could further improve the treatment with TKIs.36, 37

    Patient selectionThere are several ways to improve and personalize treatment. A first step in personalized medicine is defining patients who are likely to have a favourable prognostic outcome of treatment in terms of little side effects and long survival. These patients will potentially be the best candidates for the treatment. Patients with a poor prognostic outcome may be prevented from side effects without positive treatment effects and may possibly receive another type of treatment, which in their specific case has a better prognosis. Patient stratification may be based on tumour characteristics, as in the example of patients with GIST where patients with a specific PDGFR- mutation, D842V, have a poor response to imatinib treatment.9, 38, 39 For these patients, there are no standard treatment options available currently, but this might change in the future.

    Therapeutic drug monitoring A second possibility to further personalize treatment is by defining which dose a specific patient should get. The large differences in the occurrence of s

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