Off-label, but on target: the evidence needed to implement alternative dosing regimens of anticancer drugs

Overbeek, J K; Heine, Rob ter; Verheul, Henk M.W.; Chatelut, Étienne; Rudek, Michelle A.; Plummer, Ruth; Gilbert, Duncan C.; Buclin, Thierry; Burger, David M.; Bloemendal, Haiko J.; Erp, Nielka P. van

doi:10.1016/j.esmoop.2022.100749

Cited by 9 publications

(8 citation statements)

References 44 publications

(63 reference statements)

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“…Another important aspect to take into account is that we nd really high concentrations in vitro that might be di cult to reach in patient tumours. Although it may be simplistic to directly compare these to MC and ITC, respectively, future research should indicate whether and how in vitro exposure can be extrapolated to feasibly attainable drug levels in the clinical setting-informing the design of phase I/II studies [55,56], including the exploration of alternative ways to boost plasma and potentially tumour concentrations [57].…”

Section: Discussionmentioning

confidence: 99%

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

Iyer¹,

Poel²,

Miggelenbrink³

et al. 2023

Preprint

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Background Despite major interest in tyrosine kinase inhibitors (TKIs) as a treatment option for metastatic colorectal cancer (mCRC), almost all TKIs tested for mCRC fail in early-phase clinical trials. Although showing specific target inhibition at low concentrations, TKIs have a much broader kinase inhibitory potency at higher concentrations. In an attempt to leverage these many additional, low-affinity targets, high-dose regimens that may trigger efficacy are explored. Here, we studied unprecedented drug exposure–response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs). Methods We established patient-derived tumor organoids (PDTOs) from mCRC biopsies and, based on favorable physicochemical and pharmacokinetic properties, selected 3 TKIs (sunitinib, cediranib and osimertinib). Following standard IC50 assessment using continuous dosing with a concentration range, we investigated the cytotoxic antitumor effect of high-dose, short-term (HDST) treatment. Five PDTOs were exposed to 20 µM TKI for 1–24h, washed and given normal medium, and PDTO-outgrowth was determined 1 week later. At exposures of 1, 3 and 6 h, we measured intra-tumoroid TKI concentrations using a clinically validated LC/MS-MS method. PDTO cell death was observed using live-cell microscopy, and quantified by both caspase 3/7 enzyme activity assay and cleaved caspase-3 immunofluorescent staining. Results We show that most PDTOs tested are sensitive to multikinase TKIs sunitinib and cediranib, and all to osimertinib. Furthermore, we demonstrate that high-dose, short-term(HDST) TKI treatment effectively blocks organoid growth. In line with recent clinical data of high-dose sunitinib tumour accumulation, HDST treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. This suggests exposure-dependent cytotoxicity and supports the concept that efficacy is induced by a broad kinase inhibitory spectrum. Mechanistically, HDST osimertinib treatment for just 3 hours induced regulated cell death in treated organoids. Conclusion Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. In addition, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.

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Section: Discussionmentioning

confidence: 99%

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

Iyer¹,

Poel²,

Miggelenbrink³

et al. 2023

Preprint

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“…The suboptimal exposure associated with dosage recommendations approved at the time of commercialization of anticancer agents is increasingly recognized and justifies efforts towards dosage optimization after drug approval [35].…”

Section: Discussionmentioning

confidence: 99%

From Personalized to Precision Medicine in Oncology: A Model-Based Dosing Approach to Optimize Achievement of Imatinib Target Exposure

et al. 2023

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Imatinib is a targeted cancer therapy that has significantly improved the care of patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, it has been shown that the recommended dosages of imatinib are associated with trough plasma concentration (Cmin) lower than the target value in many patients. The aims of this study were to design a novel model-based dosing approach for imatinib and to compare the performance of this method with that of other dosing methods. Three target interval dosing (TID) methods were developed based on a previously published PK model to optimize the achievement of a target Cmin interval or minimize underexposure. We compared the performance of those methods to that of traditional model-based target concentration dosing (TCD) as well as fixed-dose regimen using simulated patients (n = 800) as well as real patients’ data (n = 85). Both TID and TCD model-based approaches were effective with about 65% of Cmin achieving the target imatinib Cmin interval of 1000–2000 ng/mL in 800 simulated patients and more than 75% using real data. The TID approach could also minimize underexposure. The standard 400 mg/24 h dosage of imatinib was associated with only 29% and 16.5% of target attainment in simulated and real conditions, respectively. Some other fixed-dose regimens performed better but could not minimize over- or underexposure. Model-based, goal-oriented methods can improve initial dosing of imatinib. Combined with subsequent TDM, these approaches are a rational basis for precision dosing of imatinib and other drugs with exposure–response relationships in oncology.

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“…Coadministration of grapefruit with the kinase inhibitor lapatinib could also reduce the dose required [54][55][56], potentially saving over €2000 per patient per month [6]. Similar avenues are being explored with other agents [57,58], though no research on clinical outcomes has been conducted; thus, these strategies are not established enough to use in our patients.…”

Section: Drug Dosing and Schedulingmentioning

confidence: 99%

Optimising oncology drug expenditure in Ireland

Kieran,

Hennessy,

Coakley

et al. 2024

Ir J Med Sci

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A combination of improvements in patient survival, increasing treatment duration, and the development of more expensive agents has led to a doubling of per-capita spending on cancer medicines in Ireland (2008–2018). Despite this, access to new drugs is poor in comparison to other EU countries. We examine methods to optimise oncology drug spending to facilitate access to newer anticancer agents. Key targets for spending optimisation (biosimilar use, clinical trials and expanded access programs, waste reduction, avoidance of futile treatment, and altered drug scheduling) were identified through an exploratory analysis. A structured literature search was performed, with a focus on articles relevant to the Irish Healthcare system, supplemented by reports from statutory bodies. At the present time, EMA-approved agents are available once approved by the NCPE. Optimising drug costs occurs through guideline-based practice and biosimilar integration, the latter provides €80 million in cost savings annually. Access to novel therapies can occur via over 50 clinical trials and 28 currently available expanded access programmes. Additional strategies include reversion to weight-based immunotherapy dosing, potentially saving €400,000 per year in our centre alone, vial sharing, and optimisation of treatment schedules. A variety of techniques are being employed by oncologists to optimise costs and increase access to innovation for patients. Use of biosimilars, drug wastage, and prescribing at end of life should be audited as key performance indicators, which may lead to reflective practice on treatment planning. Such measures could further optimise oncology drug expenditure nationally facilitating approval of new agents.

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Off-label, but on target: the evidence needed to implement alternative dosing regimens of anticancer drugs

Cited by 9 publications

References 44 publications

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

From Personalized to Precision Medicine in Oncology: A Model-Based Dosing Approach to Optimize Achievement of Imatinib Target Exposure

Optimising oncology drug expenditure in Ireland

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