A simple and rapid liquid chromatography-mass spectrometry method to assay cabozantinib in plasma: Application to therapeutic drug monitoring in patients with renal cell carcinoma
Introduction
Cabozantinib is an oral, multi-targets tyrosine kinase inhibitor targeting VEGFR1-3, AXL, MET, RET, KIT, FLT3, ROS1, MER, TYRO3, TRKB and TIE-2 that has been recently approved for treating metastatic renal clear cell carcinoma (mRCC). In the METEOR pivotal phase 3 trial [1], cabozantinib proved to increase both progression-free and overall survival in second or greater line of treatment as compared with everolimus. In the CABOSUN comparative phase 2 trial, cabozantinib performed better than sunitinib in terms of progression-free survival, thus leading to being approved (60 mg QD dosing) in Europe and the USA as first-line treatment in poor to intermediary prognostic patients with metastatic renal carcinoma [2]. As compared with other multi-targets inhibitors, the safety profile of cabozantinib is in many respects considered as a concern, leading to frequent treatment discontinuation or empirical dose reduction. In the METEOR study, 60% of dose reduction and 9% of treatment interruption were required in patients in the cabozantinib arm. In the CABOSUN study, up to 68% of grade 3–4 toxicities (i.e., diarrhea, hypertension, fatigue and AST) were reported. Most frequently reported side-effects (all-grade) are hypertension, palmar-plantar erythrodyesthesia syndrome, diarrhea, vomiting, anorexia, fatigue and oral mucositis [3]. Of note, the cabozantinib label provides a dosing algorithm for cutting initial regimen (i.e., 40 mg and 20 mg tablets) in case of intolerable toxicities in mRCC patients. In patients with thyroid cancers treated with 140 mg QD, a therapeutic window comprised between 500 and 1500 ng/ml has been proposed for cabozantinib trough levels to ensure an acceptable efficacy/toxicity balance [4]. Importantly, pharmacokinetics (PK) parameters of cabozantinib may vary from one cancer type to another, explaining the differences in dosing depending on the indication. Notably, patients with renal cell carcinoma exhibited reduced clearance values as compared with other patients and consequently, the approved dosing is 60 mg QD [5]. In addition, cabozantinib is predominantly metabolized in the liver by cytochrome P450 3A4 (CYP3A4), leading to possible large variations in cabozantinib exposure levels because of frequent drug-drug interactions in patients with multiple co-prescribed drugs, hepatic impairment, plus influence of renal impairment and food intake [6]. The scarcity of data regarding exact PK/pharmacodynamics (PD) relationships in patients with renal carcinoma, plus the multiple causes for changes in cabozantinib exposure levels and concerns regarding its safety profile, pave the way for implementing therapeutic drug monitoring (TDM) with this new drug. Several analytical methods have already been published to assay cabozantinib in biological matrix, most of them for investigational purpose such as metabolite identification or animal studies. Despite their performances, these methods do not necessarily meet the requirements for routine application in TDM such as cost-effectiveness, simplicity and time-effectiveness. To this end, here we have developed and validated a simple, rapid and easy-to-use liquid chromatography tandem mass spectrometry (LC-MS/MS) method to assay cabozantinib in plasma and monitor exposure levels in patients.
Section snippets
Chemicals and reagents
Cabozantinib and stable isotopically labelled internal standard (IS) cabozantinib 2H4 were purchased from Alsachim, Illkirch, France. Ultrapure water was obtained from a MilliQ plus purification system, Millipore, France. Acetonitrile, methanol (all UPLC grade) and formic acid were acquired from Thermo Fischer, Dardilly, France. Blank plasma for preparation quality control (QCs) samples, calibration standards and matrix blanks was acquired from the French Etablissement Français du Sang
Application for TDM in routine mRCC patients
Five ml blood samples were withdrawn as part of routine drug monitoring in our institute in 12 mRCC patients treated with cabozantinib at standard 60 mg QD dosing. Samples were collected at steady state (i.e., at least 10 days after treatment starts), and withdrawn 24 h after the last daily intake of cabozantinib (i.e., trough levels or Cmin). Plasma was isolated after centrifugation and kept frozen (-80 °C) until analysis. Sample preparation and subsequent mass spectrometry analysis was
Method validation
The method was validated in accordance with the ISO-1589 and EMEA guidelines and an overview of the validation parameters is provided in Table 1. Cabozantinib and Cabozantinib 2H4 IS were detected and quantified over a total of 5 min analytical run. The retention time for cabozantinib (m/z 502 → 323) and Cabozantinib 2H4 (m/z 506 → 323) were 1.78 and 1.79 min respectively. All tested parameters meet their previously predefined criteria as described below.
Linearity and sensitivity
The correlation coefficients (r2) for
Discussion and conclusion
Renal cell carcinoma has been a disease with dismal prognosis until sunitinib, an oral multi-targets tyrosine kinase inhibitor, was approved in 2006. Several other targeted therapies such as pazopanib, sorafenib, everolimus or axitinib have stretched the therapeutic options in kidney cancer over the last decade. Of note, since its first approval PK/PD relationships of sunitinib have been extensively studied and different target exposures (i.e., combined trough levels comprised between 50 and
CRediT authorship contribution statement
Florent Ferrer: Conceptualization, Methodology, Validation, Formal analysis, Writing - review & editing, Visualization. Caroline Solas: Formal analysis, Writing - review & editing. Madeline Giocanti: Validation, Formal analysis. Bruno Lacarelle: Writing - review & editing. Jean-Laurent Deville: Conceptualization, Investigation. Gwenaelle Gravis: Conceptualization, Investigation. Joseph Ciccolini: Conceptualization, Formal analysis, Writing - review & editing, Visualization, Supervision, Project
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Cited by (11)
Therapeutic Drug Monitoring for Tyrosine Kinase Inhibitors in Metastatic Renal Cell Carcinoma
2024, Clinical Genitourinary CancerSolid phase extraction prior to non-aqueous capillary electrophoresis with ultraviolet detection as a valuable strategy for therapeutic drug monitoring of cabozantinib
2022, Microchemical JournalCitation Excerpt :Since this is the first work reporting determination of CBZ in urine in patients under treatment, it is not possible to compare the concentrations found in the analysed sample with other reports. As general information, the levels found in urine are lower than the ones reported previously in plasma of patients undergoing the same treatment, ca. 203 – 2100 µg/L [12]. Nonetheless, a comparison in analytical terms of the proposed approach with previous methods is shown in Table 3.
Comparison of a newly developed high performance liquid chromatography method with diode array detection to a liquid chromatography tandem mass spectrometry method for the quantification of cabozantinib, dabrafenib, nilotinib and osimertinib in human serum – Application to therapeutic drug monitoring
2022, Clinical BiochemistryCitation Excerpt :Their recommended target trough levels should be detectable with HPLC-UV/DAD [6]. Whereas several LC-MS/MS methods for the quantification of CAB, DAB, NIL and OSI have been developed [7–25], to the best of our knowledge only five HPLC-UV methods for the single quantification of NIL and no methods for the quantification of CAB, DAB and OSI have been published [27–30]. Therefore, we developed and validated a cost-efficient HPLC-UV/DAD method for the simultaneous quantification and re-analyzed patient samples from clinical routine.
An overview of the clinical use of cabozantinib in the treatment of advanced non-clear-cell renal cell carcinoma (NCCRCC)
2020, Critical Reviews in Oncology/HematologyCitation Excerpt :This is potentially explained by the higher prevalence of papillary histology tumours in the NCCRCC group (Di Nunno et al., 2019). In order to avoid toxicity and unwanted drug discontinuation, liquid chromatography-tandem mass spectrometry could be used to assess cabozantinib in plasma and monitor the exposure levels of patients (Ferrer et al., 2020). Currently, cabozantinib is under evaluation in four phase II clinical trials, all in a “recruiting” status with no preliminary results available (Table 2).