European Journal of Cancer (2014) xxx, xxx– xxx
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Position Paper
Therapeutic drug monitoring in cancer – Are we missing a trick? q Christophe Bardin a,b,⇑, Gareth Veal c, Angelo Paci d, Etienne Chatelut e, Alain Astier f, Dominique Leveˆque g, Nicolas Widmer h,i, Jos Beijnen j a
Unite´ fonctionnelle de Pharmacocine´tique et Pharmacochimie, Hoˆpital Cochin, Paris, France Service de Pharmacie clinique, Hoˆpital Cochin, Paris, France c Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK d Department of Pharmacology and Drug Analysis, Gustave Roussy Cancer Campus Grand Paris, Universite´ Paris-Sud, Villejuif, France e EA4553 Institut Claudius-Regaud, Universite´ Paul-Sabatier, Toulouse, France f Department of Pharmacy, CNRS-UMR 7054, School of Medicine Paris 12, Henri Mondor University Hospitals, Cre´teil, France g Service de Pharmacie, Hoˆpital Hautepierre, Strasbourg, France h Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland i Pharmacie des Hoˆpitaux de l’Est Le´manique, Vevey, Switzerland j Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Stotervaart Hospital, Amsterdam, The Netherlands b
Received 8 April 2014; accepted 11 April 2014
KEYWORDS Therapeutic drug monitoring Cytotoxics Chemotherapy Oncology Pharmacokinetics Targeted therapies Variability Tyrosine kinase inhibitors Monoclonal antibodies Target concentration
Abstract Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/ or reduce toxicity. The cytotoxic drugs are characterised by steep dose–response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug–drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib,
q This position article is the result of a workshop carried out under the auspices of the French Society of Oncology Pharmacy (SFPO). It has been elaborated with the participation of different European experts (authors) in anticancer drugs therapeutic drug monitoring. ⇑ Corresponding author at: Unite´ fonctionnelle de Pharmacocine´tique et Pharmacochimie, Ho ˆ pital Cochin, Paris, France. Tel.: +33 158413298; fax: +33 158413286. E-mail addresses: [email protected], [email protected] (C. Bardin).
http://dx.doi.org/10.1016/j.ejca.2014.04.013 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
2
C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx
erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration–effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing. Ó 2014 Elsevier Ltd. All rights reserved.
Over five decades of research in the area of anticancer drug discovery culminated in approximately five dozen anticancer drugs with the status of licensed medicinal products around the turn of the century. These agents had very similar mechanisms of action, being directly targeted towards nucleic acid homoeostasis and leading to cell growth arrest or cell death. Lack of tumour selectivity, however, explains why these ‘classical’ anticancer drugs exhibit a broad array of adverse effects. Although many measures have been developed to reduce the sideeffects of chemotherapy, they remain a common problem and in some cases may even be life-threatening. From a clinical pharmacology viewpoint the ‘classical’ agents are characterised by steep dose–response relationships and narrow therapeutic windows, with small margins between toxic and subtherapeutic exposures. Inter-individual pharmacokinetic (PK) and pharmacodynamic (PD) variabilities are often substantial. In addition to concerns over drug safety, this also implies that undertreatment may occur in cancer patients. Oncologists usually refrain from implementing dose increases when patients do not show toxic side-effects after a standard dose of chemotherapy although this may be symptomatic of underexposure. Dosing is usually based on body surface area, commonly targeting the maximum tolerated dose. In view of the narrow therapeutic index and proven PK–PD (toxicity–antitumour activity) relationships for many anticancer drugs, it is striking that therapeutic drug monitoring (TDM) is still relatively uncommon in a cancer setting. TDM can be defined as the measurement of drug or active metabolite levels in biological samples (usually plasma) to individualise treatment by adapting drug dose and/or schedule to ultimately improve efficacy and/or reduce toxicity. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. A key factor in this respect relates to the challenges of establishing appropriate drug target concentrations or therapeutic windows, particularly when many agents are given as combination therapy and/or using contrasting dosing schedules [1]. Moreover, several widely used anticancer agents are pro-drugs and require in vivo activation to exert their biological activity. These activated metabolites are often unstable and may be formed
intracellularly, therefore not lending themselves to TDM approaches. Another important logistic requirement is the availability of appropriate equipment, assays and trained personnel to draw timed blood samples and to measure real-time drug (or activated metabolite) levels in biological samples [2]. On a related note, established chemotherapy schedules (short intravenous (i.v.) infusion every 21 days) limit the benefit of TDM since the whole dose of the corresponding cycle has been administered when plasma concentrations realistically become available. Dose adjustment according to these concentrations could therefore not be applied before the following cycle, by which time information relating to haematological tolerance is available to guide dose adjustment. Furthermore the real supplementary value of TDM in therapeutic outcome has not yet been demonstrated persuasively by performing comparative randomised trials of classic dosing (in mg/m2) versus pharmacokinetically-guided adaptive dosing. To our knowledge there are only three reports in the literature following this trial design, all of which can arguably be awarded ‘landmark study’ status. Evans et al. performed a prospective comparison of conventional fixed-dose (in mg/m2) chemotherapy with AUC (area under the plasma concentration-time curve) targeted individualised chemotherapy, including methotrexate, in childhood acute lymphoblastic leukaemia [3]. Relapse-free survival in the individualised cohort was significantly better than that in the conventional therapy group. Milano’s group in France demonstrated that an individual 5-fluorouracil adaptive dosing strategy improved the therapeutic index compared with standard dosing (in g/m2) [4]. While objective response rates were comparable in both treatment groups, toxicity was significantly reduced in the adaptive dosing group. Similarly, Gamelin and coworkers evaluated the supplementary value of 5-fluorouracil TDM in patients with metastatic colorectal cancer in a prospective phase III study [5]. The authors concluded that individual 5fluorouracil dose adjustments based on PK monitoring resulted in a significantly improved objective response rate, a trend towards a higher survival rate and fewer grade 3/4 toxicities. While results from prospective trials such as these may be pivotal to the clinical acceptance of
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx
the TDM concept for ‘classical’ anticancer drugs, for many agents such data do not exist. In the majority of cases, the experience gained in dosing patients with well-established chemotherapy regimens over many years has led to sparing implementation of TDM approaches to treatment. More recently, a new era of cancer therapy has emerged, with the treatment of several tumour types moving away from the use of cytotoxic drugs to chronic treatment with targeted molecular therapies [6]. These treatments are characterised by unique mechanisms of action and are highly specific for single or multiple key cellular biological pathways implicated in the cancer process [7]. Introduced into the clinic some 30 years ago, tamoxifen selectively modulates oestrogen receptors (ER) and thus can be considered as the first example of an oral ‘targeted’ anticancer therapy [8]. Around the turn of the century, signal transduction inhibitors (STI) were first introduced, discerned into monoclonal antibodies (mAbs) and the so-called ‘small molecule’ STI. This radical change in drug discovery was fuelled by novel insights gained into molecular biological cancer processes, which became exploitable for the rational design of new chemical entities with anticancer potency [9]. Targeted STI therapy via protein kinase inhibitors is directed against (onco)proteins, allowing the modulation of various signalling pathways, and is therefore characterised by more limited non-specific toxicities [10]. Most of these drugs are tyrosine kinase inhibitors (TKIs), with imatinib acting as the prototype drug in this class. Finally, mAbs are also now being intensively developed as parenteral targeted anticancer therapies [11] and have become one of the largest classes of new therapeutic agents approved for use in solid tumours. These therapeutic agents are now revolutionising cancer treatment by transforming previously deadly malignancies into chronically manageable conditions. Nevertheless, primary or secondary drug resistance, persistence of cancer stem cells, and drug adverse effects still limit their ability to stabilise or cure malignant diseases in the long term. In addition, poor tolerability and therapeutic failure are not uncommon, and relapse is a nearly inevitable consequence of treatment interruption [12]. Moreover, the shift to oral targeted therapies is creating new paradigms in cancer care, with drug adherence a more critical issue. It is increasingly appreciated that variability in response to newer targeted drugs is influenced not only by the genetic heterogeneity of drug targets determining tumour sensitivity, but also by inter-patient variability relating to metabolic enzyme and drug transporter pathways (e.g. cytochrome P450 [CYP] activities or ABC drug transporter polymorphisms), patient characteristics such as adherence to treatment, as well as diet and environmental factors that influence PKs [13]. In addition, drug interactions with CYP modulators are a
3
major concern with oral targeted therapies. The vast majority of targeted drugs are thus characterised by a wide spread of plasma concentrations observed following standard dosage regimens, with inter-individual variability at the end of the dosage interval (trough concentrations) of up to 23-fold [14]. Inter-individual variability of drug concentrations may favour the selection of resistant cellular clones in cases where subtherapeutic drug exposures are experienced, or the development of undesirable toxicity in cases of overexposure [12]. This may be less relevant for mAbs as they exhibit numerous PK and PD characteristics that markedly differ from those of small molecules [11,15]. However, while it is generally accepted that inter-patient PK variability observed with mAbs is lower than that observed with TKIs, preliminary clinical observations suggest that the level of variability observed is still large enough to impact on treatment efficacy. Retrospective studies have shown that exposure to targeted drugs, reflected in either the AUC or more conveniently the trough concentration (Cmin), correlates with treatment outcome in various cancers [13,14]. Very recently, Yu et al. reported exposure–response relationships and proposed pharmacokinetic targets for TKI [16]. For imatinib, the archetypal and first available TKI [17], a concentration–effect relationship has been observed in both CML [18] and GIST patients [19]. Concentration–response relationships have also been observed for various other TKIs (e.g. concentration-toxicity for nilotinib, dasatinib and erlotinib; concentration-efficacy for sunitinib, sorafenib, erlotinib and pazopanib). In the case of mAbs, while encouraging results have been reported with rituximab and cetuximab, data from the literature are currently limited, with relatively few studies providing a sufficient level of evidence to support TDM approaches. Despite the substantial PK variability reported for orally administered targeted agents, these drugs are generally licensed for use at fixed doses; although doses can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Most of these drugs would however meet almost all criteria for successful TDM implementation in clinical practice: long-term and continuous (daily) therapy, availability of appropriate bio-analytical methods for quantification in clinical samples, high and often uncomprehended inter-individual but limited intra-individual PK variability alongside consistent associations between concentration and response. They have also the potential to be involved in multiple interactions (drug–drug; drug–food) and exhibit adherence issues with lifelong treatment [14,20,21]. Finally, as these new treatments are highly expensive a very precise piloting of their regimen might well represent a benefit for public health systems. Only for imatinib however, has it been suggested that concentration thresholds be used to guide treatment [22,23].
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
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C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx
Table 1 Comparison between classical ‘cytotoxic’ anticancer drugs and ‘small molecule’ signal transduction pathway (kinase) inhibitors. Cytotoxics
New kinase inhibitors
Origin Cellular target
Serendipity/large screening/natural sources DNA, tubulin, topoisomerase
Activation Dosing Administration Schedule Pharmacokinetics Exposure parameters + sampling Interactions Adherence
Pro-drug, bio-activation Based on body surface area or body weight Intravenous Intermittent Short half-life Area under the plasma concentration-time curve (AUC); serial blood sampling Drug–drug Supervised administration
Rationally designed chemistry Signal transduction pathways/protein kinases Intrinsic activity, no bio-activation Fixed-flat dose Oral Chronic Long half-life Steady-state trough level; single blood sample Drug–drug; drug–food Problematic adherence
Levels of evidence for TDM are indeed heterogeneous among targeted drugs. Unlike some cytotoxic drugs, such as methotrexate and 5-fluorouracil, data from prospective randomised clinical trials assessing the use of TDM for targeted drugs are not yet available, but are eagerly awaited [12,16,22,24]. Table 1 lists key characteristics, in general terms, of the old ‘classical’ cytotoxic drugs versus the new ‘small molecule’ kinase inhibitors. While the benefits for pharmaceutical companies to invest in TDM may not yet be clearly identified, it is interesting to note that most failures in phase III trials are related to a lack of efficacy, with can be attributed to underdosing, as opposed to excessive toxicity [25]. To establish the use of TDM in current oncology clinical practice, several points need to be considered: Considerable effort needs to be put into the development of appropriate population PK models to better define PK variability and concentration–effect relationships of targeted therapies. Predicted therapeutic target ranges should ideally be validated prospectively through the utilisation of well-designed prospective randomised clinical trials. Technological developments towards the miniaturisation of monitoring tests and their delivery at the point-of-care might well represent a possibility to make TDM in oncology easier. With the current state of knowledge, applications for TDM during oral targeted therapy may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and/or concerns over adherence to treatment. Despite some encouraging results with mAbs, analysis of the available literature overall suggests that the TDM of mAbs is not yet supported by sufficient scientific evidence. In this context, personalised cancer care should include TDM for appropriate candidate drugs. A European workshop was recently held in France, under the auspices of the French Society of Oncology Pharmacy
(SFPO), to propose practical guidelines to improve anticancer drug TDM. The review articles included in this issue of EJC focus on anticancer drugs for which a number of studies have established relationships between plasma drug concentration and response to therapy, but also address unresolved questions relating to anticancer drug TDM and the challenges and obstacles to more effective utilisation of TDM in an oncology setting. In the future, efforts should indeed concentrate on strategies aiming at maximising the potential therapeutic benefit of oncology therapies by optimising dosage regimen in the frame of personalised medicine. Conflict of interest statement None declared. References [1] Saleem M, Dimeski G, Kirkpatrick CM, Taylor PJ, Martin JH. Target concentration intervention in oncology: where are we at? Ther Drug Monit 2012;34:257–65. [2] Beijnen JH, Rosing H. Bioanalytical methods for anticancer drugs. In: Schellens JHM, McLeod HL, Newell DR, editors. Cancer clinical pharmacology. Oxford: Oxford University Press; 2005. p. 1–17. [3] Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. New Engl J Med 1998;338:499–505. [4] Fety R, Rolland F, Barberi-Heyob M, et al. Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicenter randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res 1998;4:2039–45. [5] Gamelin E, Delva R, Jacob J, et al. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2009–105. [6] Sawyers C. Targeted cancer therapy. Nature 2004;432:294–7. [7] Giamas G, Man YL, et al. Kinases as targets in the treatment of solid tumors. Cell Signal 2010;22:984–1002. [8] Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer 2008;44:30–8.
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx [9] Beijnen JH, Schellens JHM. Personalized medicine in oncology: a personal view with myths and facts. Curr Clin Pharmacol 2010;5:141–7. [10] Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000;351:95–105. [11] Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs 2010;24:23–39. [12] Von Mehren M, Widmer N. Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): an emerging role for drug blood level testing? Cancer Treat Rev 2011;37:291–9. [13] Klumpen HJ, Samer CF, et al. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev 2011;37:251–60. [14] Gao B, Yeap S, Clements A, Balakrishnar B, Wong M, Gurney H. Evidence for therapeutic drug monitoring of targeted anticancer therapies. J Clin Oncol 2012;30:4017–25. [15] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49: 633–59. [16] Yu H, Steeghs N, Nijenhuis M, Schellens JHM, Beijnen JH, Huitema ADR. Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors; focus on the pharmacokinetic targets. Clin Pharmacokinet 2014;53: 305–35.
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[17] Horne SD, Stevens JB, Abdallah BY, et al. Why imatinib remains an exception of cancer research. J Cell Physiol 2013;228:665–70. [18] Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496–9. [19] Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/ metastatic gastrointestinal stromal tumors. J Clin Oncol 2009;27:3141–7. [20] Buclin T, Widmer N, Biollaz J, Decosterd LA. Who is in charge of assessing therapeutic drug monitoring? The case of imatinib. Lancet Oncol 2011;12:9–11. [21] Saleem M, Dimeski G, Kirkpatrick CM, Taylor PJ, Martin JH. Target concentration intervention in oncology: where are we at? Ther Drug Monit 2012;34:257–65. [22] Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther Drug Monit 2013;35:150–67. [23] Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M, ESMO Guidelines Working Group. Chronic myelogenous leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2012;23(Suppl. 7):vii72–7. [24] Josephs DH, Fisher DS, Spicer J, Flanagan RJ. Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring. Ther Drug Monit 2013;35:562–87. [25] Beumer JH. Without therapeutic drug monitoring, there is no personalized cancer care. Clin Pharmacol Ther 2013;93:228–30.
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Position Paper
Therapeutic drug monitoring in cancer – Are we missing a trick? q Christophe Bardin a,b,⇑, Gareth Veal c, Angelo Paci d, Etienne Chatelut e, Alain Astier f, Dominique Leveˆque g, Nicolas Widmer h,i, Jos Beijnen j a
Unite´ fonctionnelle de Pharmacocine´tique et Pharmacochimie, Hoˆpital Cochin, Paris, France Service de Pharmacie clinique, Hoˆpital Cochin, Paris, France c Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK d Department of Pharmacology and Drug Analysis, Gustave Roussy Cancer Campus Grand Paris, Universite´ Paris-Sud, Villejuif, France e EA4553 Institut Claudius-Regaud, Universite´ Paul-Sabatier, Toulouse, France f Department of Pharmacy, CNRS-UMR 7054, School of Medicine Paris 12, Henri Mondor University Hospitals, Cre´teil, France g Service de Pharmacie, Hoˆpital Hautepierre, Strasbourg, France h Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland i Pharmacie des Hoˆpitaux de l’Est Le´manique, Vevey, Switzerland j Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Stotervaart Hospital, Amsterdam, The Netherlands b
Received 8 April 2014; accepted 11 April 2014
KEYWORDS Therapeutic drug monitoring Cytotoxics Chemotherapy Oncology Pharmacokinetics Targeted therapies Variability Tyrosine kinase inhibitors Monoclonal antibodies Target concentration
Abstract Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/ or reduce toxicity. The cytotoxic drugs are characterised by steep dose–response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug–drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib,
q This position article is the result of a workshop carried out under the auspices of the French Society of Oncology Pharmacy (SFPO). It has been elaborated with the participation of different European experts (authors) in anticancer drugs therapeutic drug monitoring. ⇑ Corresponding author at: Unite´ fonctionnelle de Pharmacocine´tique et Pharmacochimie, Ho ˆ pital Cochin, Paris, France. Tel.: +33 158413298; fax: +33 158413286. E-mail addresses: [email protected], [email protected] (C. Bardin).
http://dx.doi.org/10.1016/j.ejca.2014.04.013 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
2
C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx
erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration–effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing. Ó 2014 Elsevier Ltd. All rights reserved.
Over five decades of research in the area of anticancer drug discovery culminated in approximately five dozen anticancer drugs with the status of licensed medicinal products around the turn of the century. These agents had very similar mechanisms of action, being directly targeted towards nucleic acid homoeostasis and leading to cell growth arrest or cell death. Lack of tumour selectivity, however, explains why these ‘classical’ anticancer drugs exhibit a broad array of adverse effects. Although many measures have been developed to reduce the sideeffects of chemotherapy, they remain a common problem and in some cases may even be life-threatening. From a clinical pharmacology viewpoint the ‘classical’ agents are characterised by steep dose–response relationships and narrow therapeutic windows, with small margins between toxic and subtherapeutic exposures. Inter-individual pharmacokinetic (PK) and pharmacodynamic (PD) variabilities are often substantial. In addition to concerns over drug safety, this also implies that undertreatment may occur in cancer patients. Oncologists usually refrain from implementing dose increases when patients do not show toxic side-effects after a standard dose of chemotherapy although this may be symptomatic of underexposure. Dosing is usually based on body surface area, commonly targeting the maximum tolerated dose. In view of the narrow therapeutic index and proven PK–PD (toxicity–antitumour activity) relationships for many anticancer drugs, it is striking that therapeutic drug monitoring (TDM) is still relatively uncommon in a cancer setting. TDM can be defined as the measurement of drug or active metabolite levels in biological samples (usually plasma) to individualise treatment by adapting drug dose and/or schedule to ultimately improve efficacy and/or reduce toxicity. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. A key factor in this respect relates to the challenges of establishing appropriate drug target concentrations or therapeutic windows, particularly when many agents are given as combination therapy and/or using contrasting dosing schedules [1]. Moreover, several widely used anticancer agents are pro-drugs and require in vivo activation to exert their biological activity. These activated metabolites are often unstable and may be formed
intracellularly, therefore not lending themselves to TDM approaches. Another important logistic requirement is the availability of appropriate equipment, assays and trained personnel to draw timed blood samples and to measure real-time drug (or activated metabolite) levels in biological samples [2]. On a related note, established chemotherapy schedules (short intravenous (i.v.) infusion every 21 days) limit the benefit of TDM since the whole dose of the corresponding cycle has been administered when plasma concentrations realistically become available. Dose adjustment according to these concentrations could therefore not be applied before the following cycle, by which time information relating to haematological tolerance is available to guide dose adjustment. Furthermore the real supplementary value of TDM in therapeutic outcome has not yet been demonstrated persuasively by performing comparative randomised trials of classic dosing (in mg/m2) versus pharmacokinetically-guided adaptive dosing. To our knowledge there are only three reports in the literature following this trial design, all of which can arguably be awarded ‘landmark study’ status. Evans et al. performed a prospective comparison of conventional fixed-dose (in mg/m2) chemotherapy with AUC (area under the plasma concentration-time curve) targeted individualised chemotherapy, including methotrexate, in childhood acute lymphoblastic leukaemia [3]. Relapse-free survival in the individualised cohort was significantly better than that in the conventional therapy group. Milano’s group in France demonstrated that an individual 5-fluorouracil adaptive dosing strategy improved the therapeutic index compared with standard dosing (in g/m2) [4]. While objective response rates were comparable in both treatment groups, toxicity was significantly reduced in the adaptive dosing group. Similarly, Gamelin and coworkers evaluated the supplementary value of 5-fluorouracil TDM in patients with metastatic colorectal cancer in a prospective phase III study [5]. The authors concluded that individual 5fluorouracil dose adjustments based on PK monitoring resulted in a significantly improved objective response rate, a trend towards a higher survival rate and fewer grade 3/4 toxicities. While results from prospective trials such as these may be pivotal to the clinical acceptance of
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx
the TDM concept for ‘classical’ anticancer drugs, for many agents such data do not exist. In the majority of cases, the experience gained in dosing patients with well-established chemotherapy regimens over many years has led to sparing implementation of TDM approaches to treatment. More recently, a new era of cancer therapy has emerged, with the treatment of several tumour types moving away from the use of cytotoxic drugs to chronic treatment with targeted molecular therapies [6]. These treatments are characterised by unique mechanisms of action and are highly specific for single or multiple key cellular biological pathways implicated in the cancer process [7]. Introduced into the clinic some 30 years ago, tamoxifen selectively modulates oestrogen receptors (ER) and thus can be considered as the first example of an oral ‘targeted’ anticancer therapy [8]. Around the turn of the century, signal transduction inhibitors (STI) were first introduced, discerned into monoclonal antibodies (mAbs) and the so-called ‘small molecule’ STI. This radical change in drug discovery was fuelled by novel insights gained into molecular biological cancer processes, which became exploitable for the rational design of new chemical entities with anticancer potency [9]. Targeted STI therapy via protein kinase inhibitors is directed against (onco)proteins, allowing the modulation of various signalling pathways, and is therefore characterised by more limited non-specific toxicities [10]. Most of these drugs are tyrosine kinase inhibitors (TKIs), with imatinib acting as the prototype drug in this class. Finally, mAbs are also now being intensively developed as parenteral targeted anticancer therapies [11] and have become one of the largest classes of new therapeutic agents approved for use in solid tumours. These therapeutic agents are now revolutionising cancer treatment by transforming previously deadly malignancies into chronically manageable conditions. Nevertheless, primary or secondary drug resistance, persistence of cancer stem cells, and drug adverse effects still limit their ability to stabilise or cure malignant diseases in the long term. In addition, poor tolerability and therapeutic failure are not uncommon, and relapse is a nearly inevitable consequence of treatment interruption [12]. Moreover, the shift to oral targeted therapies is creating new paradigms in cancer care, with drug adherence a more critical issue. It is increasingly appreciated that variability in response to newer targeted drugs is influenced not only by the genetic heterogeneity of drug targets determining tumour sensitivity, but also by inter-patient variability relating to metabolic enzyme and drug transporter pathways (e.g. cytochrome P450 [CYP] activities or ABC drug transporter polymorphisms), patient characteristics such as adherence to treatment, as well as diet and environmental factors that influence PKs [13]. In addition, drug interactions with CYP modulators are a
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major concern with oral targeted therapies. The vast majority of targeted drugs are thus characterised by a wide spread of plasma concentrations observed following standard dosage regimens, with inter-individual variability at the end of the dosage interval (trough concentrations) of up to 23-fold [14]. Inter-individual variability of drug concentrations may favour the selection of resistant cellular clones in cases where subtherapeutic drug exposures are experienced, or the development of undesirable toxicity in cases of overexposure [12]. This may be less relevant for mAbs as they exhibit numerous PK and PD characteristics that markedly differ from those of small molecules [11,15]. However, while it is generally accepted that inter-patient PK variability observed with mAbs is lower than that observed with TKIs, preliminary clinical observations suggest that the level of variability observed is still large enough to impact on treatment efficacy. Retrospective studies have shown that exposure to targeted drugs, reflected in either the AUC or more conveniently the trough concentration (Cmin), correlates with treatment outcome in various cancers [13,14]. Very recently, Yu et al. reported exposure–response relationships and proposed pharmacokinetic targets for TKI [16]. For imatinib, the archetypal and first available TKI [17], a concentration–effect relationship has been observed in both CML [18] and GIST patients [19]. Concentration–response relationships have also been observed for various other TKIs (e.g. concentration-toxicity for nilotinib, dasatinib and erlotinib; concentration-efficacy for sunitinib, sorafenib, erlotinib and pazopanib). In the case of mAbs, while encouraging results have been reported with rituximab and cetuximab, data from the literature are currently limited, with relatively few studies providing a sufficient level of evidence to support TDM approaches. Despite the substantial PK variability reported for orally administered targeted agents, these drugs are generally licensed for use at fixed doses; although doses can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Most of these drugs would however meet almost all criteria for successful TDM implementation in clinical practice: long-term and continuous (daily) therapy, availability of appropriate bio-analytical methods for quantification in clinical samples, high and often uncomprehended inter-individual but limited intra-individual PK variability alongside consistent associations between concentration and response. They have also the potential to be involved in multiple interactions (drug–drug; drug–food) and exhibit adherence issues with lifelong treatment [14,20,21]. Finally, as these new treatments are highly expensive a very precise piloting of their regimen might well represent a benefit for public health systems. Only for imatinib however, has it been suggested that concentration thresholds be used to guide treatment [22,23].
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
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C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx
Table 1 Comparison between classical ‘cytotoxic’ anticancer drugs and ‘small molecule’ signal transduction pathway (kinase) inhibitors. Cytotoxics
New kinase inhibitors
Origin Cellular target
Serendipity/large screening/natural sources DNA, tubulin, topoisomerase
Activation Dosing Administration Schedule Pharmacokinetics Exposure parameters + sampling Interactions Adherence
Pro-drug, bio-activation Based on body surface area or body weight Intravenous Intermittent Short half-life Area under the plasma concentration-time curve (AUC); serial blood sampling Drug–drug Supervised administration
Rationally designed chemistry Signal transduction pathways/protein kinases Intrinsic activity, no bio-activation Fixed-flat dose Oral Chronic Long half-life Steady-state trough level; single blood sample Drug–drug; drug–food Problematic adherence
Levels of evidence for TDM are indeed heterogeneous among targeted drugs. Unlike some cytotoxic drugs, such as methotrexate and 5-fluorouracil, data from prospective randomised clinical trials assessing the use of TDM for targeted drugs are not yet available, but are eagerly awaited [12,16,22,24]. Table 1 lists key characteristics, in general terms, of the old ‘classical’ cytotoxic drugs versus the new ‘small molecule’ kinase inhibitors. While the benefits for pharmaceutical companies to invest in TDM may not yet be clearly identified, it is interesting to note that most failures in phase III trials are related to a lack of efficacy, with can be attributed to underdosing, as opposed to excessive toxicity [25]. To establish the use of TDM in current oncology clinical practice, several points need to be considered: Considerable effort needs to be put into the development of appropriate population PK models to better define PK variability and concentration–effect relationships of targeted therapies. Predicted therapeutic target ranges should ideally be validated prospectively through the utilisation of well-designed prospective randomised clinical trials. Technological developments towards the miniaturisation of monitoring tests and their delivery at the point-of-care might well represent a possibility to make TDM in oncology easier. With the current state of knowledge, applications for TDM during oral targeted therapy may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and/or concerns over adherence to treatment. Despite some encouraging results with mAbs, analysis of the available literature overall suggests that the TDM of mAbs is not yet supported by sufficient scientific evidence. In this context, personalised cancer care should include TDM for appropriate candidate drugs. A European workshop was recently held in France, under the auspices of the French Society of Oncology Pharmacy
(SFPO), to propose practical guidelines to improve anticancer drug TDM. The review articles included in this issue of EJC focus on anticancer drugs for which a number of studies have established relationships between plasma drug concentration and response to therapy, but also address unresolved questions relating to anticancer drug TDM and the challenges and obstacles to more effective utilisation of TDM in an oncology setting. In the future, efforts should indeed concentrate on strategies aiming at maximising the potential therapeutic benefit of oncology therapies by optimising dosage regimen in the frame of personalised medicine. Conflict of interest statement None declared. References [1] Saleem M, Dimeski G, Kirkpatrick CM, Taylor PJ, Martin JH. Target concentration intervention in oncology: where are we at? Ther Drug Monit 2012;34:257–65. [2] Beijnen JH, Rosing H. Bioanalytical methods for anticancer drugs. In: Schellens JHM, McLeod HL, Newell DR, editors. Cancer clinical pharmacology. Oxford: Oxford University Press; 2005. p. 1–17. [3] Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. New Engl J Med 1998;338:499–505. [4] Fety R, Rolland F, Barberi-Heyob M, et al. Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicenter randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res 1998;4:2039–45. [5] Gamelin E, Delva R, Jacob J, et al. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2009–105. [6] Sawyers C. Targeted cancer therapy. Nature 2004;432:294–7. [7] Giamas G, Man YL, et al. Kinases as targets in the treatment of solid tumors. Cell Signal 2010;22:984–1002. [8] Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer 2008;44:30–8.
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
C. Bardin et al. / European Journal of Cancer xxx (2014) xxx–xxx [9] Beijnen JH, Schellens JHM. Personalized medicine in oncology: a personal view with myths and facts. Curr Clin Pharmacol 2010;5:141–7. [10] Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000;351:95–105. [11] Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs 2010;24:23–39. [12] Von Mehren M, Widmer N. Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): an emerging role for drug blood level testing? Cancer Treat Rev 2011;37:291–9. [13] Klumpen HJ, Samer CF, et al. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev 2011;37:251–60. [14] Gao B, Yeap S, Clements A, Balakrishnar B, Wong M, Gurney H. Evidence for therapeutic drug monitoring of targeted anticancer therapies. J Clin Oncol 2012;30:4017–25. [15] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49: 633–59. [16] Yu H, Steeghs N, Nijenhuis M, Schellens JHM, Beijnen JH, Huitema ADR. Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors; focus on the pharmacokinetic targets. Clin Pharmacokinet 2014;53: 305–35.
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[17] Horne SD, Stevens JB, Abdallah BY, et al. Why imatinib remains an exception of cancer research. J Cell Physiol 2013;228:665–70. [18] Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496–9. [19] Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/ metastatic gastrointestinal stromal tumors. J Clin Oncol 2009;27:3141–7. [20] Buclin T, Widmer N, Biollaz J, Decosterd LA. Who is in charge of assessing therapeutic drug monitoring? The case of imatinib. Lancet Oncol 2011;12:9–11. [21] Saleem M, Dimeski G, Kirkpatrick CM, Taylor PJ, Martin JH. Target concentration intervention in oncology: where are we at? Ther Drug Monit 2012;34:257–65. [22] Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther Drug Monit 2013;35:150–67. [23] Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M, ESMO Guidelines Working Group. Chronic myelogenous leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2012;23(Suppl. 7):vii72–7. [24] Josephs DH, Fisher DS, Spicer J, Flanagan RJ. Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring. Ther Drug Monit 2013;35:562–87. [25] Beumer JH. Without therapeutic drug monitoring, there is no personalized cancer care. Clin Pharmacol Ther 2013;93:228–30.
Please cite this article in press as: Bardin C. et al., Therapeutic drug monitoring in cancer – Are we missing a trick?, Eur J Cancer (2014), http:// dx.doi.org/10.1016/j.ejca.2014.04.013
