Unraveling the complexity of therapeutic drug monitoring for monoclonal antibody therapies to individualize dose in oncology

Chatelut, Étienne; Hendrikx, Jeroen J M A; Martin, Jennifer; Ciccolini, Joseph; Moes, Dirk Jan A R

doi:10.1002/prp2.757

Cited by 22 publications

(12 citation statements)

References 56 publications

(139 reference statements)

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“…TDM was typically considered advantageous for drugs with a large inter-individual variability in exposure with relatively low intra-individual variation, a significant exposure-efficacy relationship, a narrow therapeutic window, and availability of a validated bioanalytical assay [22]. It has been postulated recently that this could also represent a useful tool to individualize dosing and optimize treatment using drugs with a wide therapeutic window and high cost [54][55][56].…”

Section: Discussionmentioning

confidence: 99%

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

et al. 2022

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Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

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Section: Discussionmentioning

confidence: 99%

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

et al. 2022

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“…Eventually, this could reduce drug costs by preventing excessive treatment. TDM with PK modeling and simulation along with randomized prospective trials are needed to verify if precision medicine can be part of immunotherapy [31]. Creating a clinical application of TDM first requires an expansion of the evidence base, then simplifying sampling strategies, such as using dried blood spots or body fluids other than blood.…”

Section: Discussionmentioning

confidence: 99%

UPLC-MS/MS-Based Analysis of Trastuzumab in Plasma Samples: Application in Breast Cancer Patients Sample Monitoring

et al. 2022

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Trastuzumab is a target-based recombinant humanized IgG1 monoclonal antibody (mAbs), extensively employed for treatment of metastatic breast cancer with human epidermal growth receptor 2 (HER2) overexpression. Studies around the world have reported that mAbs have substantial inter-patient unpredictable absorption, distribution, metabolism, and excretion (ADME-pharmacokinetics) because of multiple elements manipulating the concentration of mAbs in plasma. Herein, we have established a bioanalytical technique using UPLC-MS/MS with an easy sample workup method and in-solution digestion protocol to assay the trastuzumab plasma samples from breast cancer patients in clinical studies. Surrogated proteolytic peptides were used for accurate quantification of trastuzumab (CanMab) with a trastuzumab signature peptide with [13C6, 15N4]-arginine and [13C6,15N2]-lysine stable isotope-labeled (SIL) peptide. Experiments to validate the method were accurately carried out according to the guidelines mentioned in the bioanalytical method validation protocol. The evaluation established excellent linearity over a wide range of 5–500 µg/mL. The experimental procedure was efficaciously performed in a pilot study of five breast cancer patients and residual concentrations of drugs from responding and non-responding subjects were compared. The receiver operating characteristic (ROC) examination displayed that 52.25 µg/mL was the Cmin threshold predictive response with a satisfactory sensitivity of 88.58% and specificity of 79.25%.

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“…Over the last decade, the literature about pharmacokinetics and pharmacodynamics of mAbs used in oncology has significantly expanded [ 32 , 33 , 34 ]. A large inter-individual variability in pharmacokinetics parameters and subsequent exposure levels is usually reported, regardless of the type of mAbs considered.…”

Section: Discussionmentioning

confidence: 99%

Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study

et al. 2021

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Background: Different liquid chromatography tandem mass spectrometry (LC–MS/MS) methods have been published for quantification of monoclonal antibodies (mAbs) in plasma but thus far none allowed the simultaneous quantification of several mAbs, including immune checkpoint inhibitors. We developed and validated an original multiplex LC–MS/MS method using a ready-to-use kit to simultaneously assay 7 mAbs (i.e., bevacizumab, cetuximab, ipilimumab, nivolumab, pembrolizumab, rituximab and trastuzumab) in plasma. This method was next cross-validated with respective reference methods (ELISA or LC–MS/MS). Methods: The mAbXmise kit was used for mAb extraction and full-length stable-isotope-labeled antibodies as internal standards. The LC–MS/MS method was fully validated following current EMA guidelines. Each cross validation between reference methods and ours included 16–28 plasma samples from cancer patients. Results: The method was linear from 2 to 100 µg/mL for all mAbs. Inter- and intra-assay precision was <14.6% and accuracy was 90.1–111.1%. The mean absolute bias of measured concentrations between multiplex and reference methods was 10.6% (range 3.0–19.9%). Conclusions: We developed and cross-validated a simple, accurate and precise method that allows the assay of up to 7 mAbs. Furthermore, the present method is the first to offer a simultaneous quantification of three immune checkpoint inhibitors likely to be associated in patients.

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Unraveling the complexity of therapeutic drug monitoring for monoclonal antibody therapies to individualize dose in oncology

Cited by 22 publications

References 56 publications

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

UPLC-MS/MS-Based Analysis of Trastuzumab in Plasma Samples: Application in Breast Cancer Patients Sample Monitoring

Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study

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