Simulation-Based Interpretation of Therapeutically Monitored Cabozantinib Plasma Concentration in Advanced Adrenocortical Carcinoma with Hemodialysis
Sebastian Zimmermann,* Max Kurlbaum, PhD,f# Stefanie Mayer,§ Martin Fassnacht, MD,11 Matthias Kroiss, MD, PhD, }}| and Oliver Scherf-Clavel, PhD*
Background: Adrenocortical carcinoma is an orphan but aggres- sive malignancy with limited treatment options. Cabozantinib (CAB), a tyrosine kinase inhibitor, has emerged as a new potential treatment. However, no data are available on whether and how CAB can be administered to patients undergoing hemodialysis.
Methods: An liquid chromatography with tandem mass spectrometry detection method was developed and validated accord- ing to the European Medicines Agency and United States Food and Drug Administration guidelines for bioanalytical method validation. The samples were prepared using protein precipitation and online solid-phase extraction. The method was applied to clinical samples of an adrenocortical carcinoma patient receiving CAB treatment
Received for publication March 10, 2021; accepted April 30, 2021.
From the *Department of Clinical Pharmacy Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany; ¡ Department of Internal Medicine I, Division of Endocrinology/Diabetology, University Hospital, University of Würzburg, Würzburg, Germany. Dr. Kroiss is now with the Department of Medicine IV, University Hospital Munich, Ludwig- Maximilians-Universität München, Munich, Germany; ¿ Core Unit Clinical Mass Spectrometry, University Hospital, University of Würzburg, Würzburg, Germany; §Department of Internal Medicine I, Division of Nephrology, University Hospital, University of Würzburg, Würzburg, Germany; and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
Supported by the German Research Foundation (project 314061271-TRR 205) and Hector Stiftung II gGmbH (Weinheim, Germany, Project MED 1807).
S. Zimmermann and M. Kurlbaum have contributed equally.
O. Scherf-Clavel reported a professorship grant (Horphag Research Ltd.) and received funding from the Hector Stiftung II gGmbH. M. Kroiss received institutional grant support and travel support from Ipsen Pharma GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.drug-monitoring. com).
This study was part of the European Network for the Study of Adrenal Tumors (ENSAT) registry, which has been approved by the Ethics Committee of the University of Würzburg (approval numbers 86/03 and 88/11). The study was performed in accordance with the ethical standards of the Declaration of Helsinki of 1964 and its later amendments. All participants and their authorized representatives provided written informed consent and assent before inclusion in this study.
Correspondence: Oliver Scherf-Clavel, PhD, Institute for Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany (e-mail: oliver.scherf-clavel@uni-wuerzburg.de).
Copyright @ 2021 Wolters Kluwer Health, Inc. All rights reserved.
(80 mg daily). During the 10 days of observation, the patient received periodic hemodialysis on 7 days. Pharmacokinetic (PK) simulations were performed using Bayesian forecasting according to an existing population PK model for CAB.
Results: Based on the PK simulation, a mean plasma trough concentration of 1375 ng/ml [90% prediction interval (PI), 601- 2602 ng/ml] in the steady state at a daily dose of 80 mg was expected for CAB. However, an individual simulation involving the measured plasma levels of the patient resulted in a mean trough concentration of 348 ng/ml (90% PI, 278-430 ng/ml). The model based on individual PK parameters estimated accessible plasma lev- els of 521, 625, and 834 ng/ml by dose adjustment to 100, 120, and 160 mg, respectively.
Conclusions: After establishing an liquid chromatography with tandem mass spectrometry detection method for therapeutic drug monitoring of CAB, our analyses involving a single patient undergoing hemodialysis indicated that higher than expected doses of CAB were required to achieve reasonable plasma concentrations. Our study demonstrates the usefulness of therapeutic drug monitor- ing for the evaluation of “new” drugs in patients with renal impairment.
Key Words: therapeutic drug monitoring, adrenocortical carcinoma, tyrosine kinase inhibitor, cabozantinib, personalized medicine
(Ther Drug Monit 2021;43:706-711)
BACKGROUND
Adrenocortical carcinoma (ACC) is an orphan malignant disease of the adrenal cortex with a reported incidence of up to 2 cases per million per year. Sixty percent of the cases of malignant neoplasms secrete cortical steroids,1,2 whereas 40% are nonfunctional and poorly differentiated. This hypersecretion of steroid hormones is often characterized by excess of cortisol and sex hormones, resulting in Cushing syndrome and viriliza- tion. In most cases, surgical removal of a localized tumor is the only curative therapy. Nevertheless, the majority of patients already have metastases at the time of primary diagnosis or develop metastases during their disease. Mitotane, an adreno- static agent, is the only approved drug, and it is used in an adjuvant setting3 and for advanced disease.1,2,4,5 Standard ther- apy for advanced stages is the combination of mitotane with etoposide, doxorubicin, and cisplatin.6 However, the objective response (23%) and 5-year survival rate (10%-15%) are poor, necessitating new and more effective treatment options.
Therefore, several novel targeted anticancer drugs, such as tyro- sine kinase inhibitors (TKIs), came into the focus and have been investigated in case series and clinical trials.7-13 Cabozantinib (CAB) is a multikinase receptor antagonist of vascular endothe- lial growth factor receptor (VEGFR), hepatocyte growth factor receptor kinase (HGFR), and other tyrosine kinases, such as AXL and RET.14-16 CAB is currently approved for the treatment of medullary thyroid carcinoma (MTC), advanced renal cell carcinoma (RCC), and hepatocellular carcinoma. As VEGFR and HGFR are often highly overexpressed in the tumor tissue, CAB may be effective as a treatment for ACC, and clinical trials are ongoing.17-20
Only very limited data on the plasma levels and pharmacokinetics (PKs) of TKIs are available. Unfortunately, less information is available for patients with specific clinical conditions. Thus, there are no data on patients undergoing hemodialysis, making therapy with TKIs nearly inaccessible. Recently, in the context of a study evaluating the response of CAB for the treatment of advanced ACC for a subset of 5 patients, the plasma steady-state levels were collected. Extensive interindividual variability in plasma concentrations was observed, possibly related to CYP3A4 metabolism altered by previous or concomitant medication.13 The complexity of the pharmacology of TKIs further increases as receptor activities of the main CAB metabolites (monohydroxy-CAB, CAB-N- oxide, 6-amide cleavage product) are greatly reduced, but they still show inhibition of other enzymes and transporters, such as CYP2C8 and organic anion transporter.21 As a consequence of the concomitant use of medications, the risk of drug-drug inter- action (DDI), which may result in clinically relevant adverse effects or subtherapeutic exposure and the development of receptor resistance, highly increases.22 Moreover, disorders such as renal or hepatic impairment further increase the variability of the PKs of TKIs. These mechanisms considerably affect thera- peutic success and safety.23 Therapeutic drug monitoring (TDM) facilitates the minimization of the risks of adverse effects and treatment failure by individually optimizing drug exposure24 as demonstrated for several TKIs. Based on the metabolic pathway, PK variability, or the relationship between PK and pharmaco- dynamics, TDM has been proposed to be useful for most kinase inhibitors, although this needs further corroboration for CAB.25,26
In this study, we developed and validated an liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) method to quantify CAB in human plasma. This method was used to monitor drug exposure in a patient with advanced ACC and end-stage renal disease, who was undergoing daily hemodialysis and using concomitant med- ications. These results were contextualized with simulated data obtained using a population pharmacokinetics (popPK) modeling approach.
MATERIALS AND METHODS
Chemicals
CAB-(S)-malate was purchased from Biozol (Eching, Germany). Isotope-labeled internal standard (IS) CAB-d4 was purchased from Alsachim (Illkirch Graffenstaden, France). High
performance liquid chromatography-grade acetonitrile (ACN), LC-MS grade water, and methanol (MeOH) were obtained from VWR International (Darmstadt, Germany). Dimethyl sulfoxide and formic acid (purity > 98%) were purchased from Merck (Darmstadt, Germany). Analyte-free plasma was obtained from the University Hospital of Würzburg (Würzburg, Germany).
Instrumentation and Chromatographic Condition
The LC-MS/MS system consisted of a Sciex QTRAP 4500 MD (Framingham, MA) linked to an Agilent 1290 UHPLC system (Waldbronn, Germany). The mobile phase for the high performance liquid chromatography analysis involved (1) water containing 2% ACN and 0.1% formic acid (vol/vol/vol) and (2) ACN containing 2% water and 0.1% formic (vol/vol/vol). Chromatography was performed with an XBridge BEH C18 column (3.5 um, 2.1 x 50 mm; Waters, Milford, MA) during the stationary phase in combination with an Oasis HLB column (25 pm, 2.1 x 20 mm; Waters) for the online solid-phase extraction. The gradient flow was set at 400 µL/min and increased from the 10% mobile phase B at the beginning of the acquisition to 75% B. The acquisition ended after 7.50 minutes at the starting conditions (see S1, Supplemental Digital Content, http://links.lww.com/TDM/ A496). CAB and CAB-d4 were detected in electrospray ionization-positive mode using multiple reaction monitoring 502.2 → 391.4 m/z for CAB and 506.0 → 391.4 m/z for CAB-d4. The collision energy was set to 40 eV for both transitions. Analyst software (version 1.6.3 MD) was used for the peak area-related quantification.
Sample Preparation
Ten calibrators (CR) within the calibration range of 6- 1000 ng/ml and 5 quality control (QC) levels of human plasma were prepared by serial dilution. Details on the preparation of the stock solution, CR, and QC are given in the Supplemental Digital Content (see, Supplementary Materials and Methods, http://links.lww.com/TDM/A496). The sample was prepared using protein precipitation with MeOH/ACN (1:1, vol/vol). Fifty microliters of plasma (CR, QC or sample) and 100 µL of the precipitation agent, including CAB-d4 (0.2 mcg/ mL), were mixed in a 1.5 mL polypropylene tube. After 5 seconds of vortexing and subsequent centrifugation for 5 minutes at 14,000g at 4℃, 50 ML of the supernatant and 150 ML of water were mixed and transferred into a glass vial with an insert (polypropylene). The autosampler temperature was set at 4℃ and the injection volume was 20 µL.
Method Validation
The method was validated according to the United States Food and Drug Administration and European Medicines Agency (EMA) guidelines on bioanalytical method valida- tion.27,28 The validation measures included linearity, accuracy and precision, sensitivity, selectivity, dilution integrity, the extent of carryover and matrix effects, and recovery and stabil- ity. The analytical method was cross-validated in collaboration with Radboud University, Nijmegen, the Netherlands.29
Patient Characteristics and Plasma Sampling
Plasma samples were obtained from a 34-year-old female patient (80 kg body weight) treated with 80-mg COMETRIQ capsules once daily. The patient was diagnosed with hormonally active ENSAT stage II ACC (T2N0M0). After adjuvant mitotane treatment, she developed advanced disease and received additional cytostatic treatment. During chemotherapy, the patient developed chronic kidney failure and required chronic hemodialysis. Before the CAB treat- ment, mitotane was discontinued, and the mitotane plasma concentration was undetectable before the initiation of CAB (for concomitant medication, see S2, Supplemental Digital Content, http://links.lww.com/TDM/A496). TKI exposure was monitored for 10 days. Four plasma samples (different sampling times) were collected on days 1-4 during routine blood draw: 2 samples were obtained on days 5 and 6, and 1 plasma sample was obtained on day 7. Periodic hemodialysis was performed each day, except on days 2, 6, and 9.
PK Simulation
R software and its mrgsolve package (version 0.11.0, Kyle Baron, Metrum Research Group) were used to simulate the CAB plasma levels according to a published popPK model for CAB in various cancer types.30 The popPK model did not contain data on ACC; therefore, the disease covariate “other” was used for the simulation. The individual PK parameters and their random effects on apparent clearance (1), apparent volume of distribution (12), relative oral bio- availability (13), and absorption rate (14) were determined using the maximum a posteriori and Markov chain Monte Carlo estimation implemented in R. After determining the PK parameters of the patients, the most likely steady-state plasma levels for possible dose adjustments were determined prospectively.
RESULTS
Method Validation
The method was successfully validated according to the regulatory guidelines. The validation results are presented in Supplemental Digital Content (see S3-S5 and Supplementary results, http://links.lww.com/TDM/A496).
PK Simulation
The CAB steady-state trough concentration was simulated for a reference population of 1000 cases according to the backgrounds of the patients (covariates: sex, race, weight, drug formulation, malignancy, age, dose, and liver function). The expected mean plasma concentration was 1375 ng/ml for a daily dose of 80 mg CAB capsules. The 90% prediction interval (PI) ranged from 601 to 2602 ng/mL. The measured CAB values on days 1-5 were included in the initial model to simulate the most likely individual plasma course. The CAB exposure in this patient was lower than the predicted concentration (Fig. 1A). The individual PK parameters were compared with the simu- lated population parameters according to the disease covariate “other.” The apparent patient clearance (7.71 L/h) was higher than expected (typical value: 2.41 L/h), and the apparent
individual distribution volume was 316.06 L, twice as high as in the reference collective (161.20 L) (see S6, Supplemental Digital Content, http://links.lww.com/TDM/A496). The indi- vidual random effect distribution showed that the random effects on apparent clearance (11) and apparent volume of distribution (12) deviated from the reference collective, whereas the random effects on relative oral availability (13) and absorption rate (14) could not be estimated with a higher precision during the in silico simulation. However, the measured concentrations pro- vided information for reestimating the individual clearance and volume of distribution. From the initial simulation, which included individual sample concentrations before the steady state, the estimated mean trough plasma concentration for the individual steady state was 348 ng/ml (90% PI, 278-430 ng/ mL) (Figs. 1B, C). The measured plasma trough concentrations on days 8, 9, and 10 (383, 406, and 405 ng/ml, respectively) were within the predicted range (Fig. 1B) and at a steady state. According to the individual PK parameters of this patient, the simulated mean trough concentration for an increased dosage of 100 mg, 120 mg, and 160 mg daily would have been 521, 625, and 834 ng/mL, respectively (Fig. 2). The dosage adaptation was not performed. At the beginning and after 3 months of CAB therapy, tissue imaging scans were obtained and used to assess the tumor status and the therapeutic response, and a reduction in the size and amount of tumor tissue was monitored throughout the evaluated period.
DISCUSSION
TKIs play an important role in targeted therapy for various malignant diseases. Data on PK are still limited, especially in the context of DDI and renal impairment. In the absence of data on hemodialysis, responsible therapy with TKIs requires an individualized consideration of drug expo- sure. Prospective monitoring may contribute to the optimiza- tion of therapy, particularly for this patient subpopulation, and it enables safe access to novel treatment options.
The trough levels in this study were 383, 406, and 405 ng/ml, which were significantly lower than the expected values (1054 ng/ml after 10 days; 90% PI, 509-1757 ng/ml) based on the popPK simulation and published data. Renal failure, hemodialysis, and the large number of coadministered drugs that hold the potential for DDI related to CYP3A4 (inhibition or induction) are plausible reasons for the devia- tion in plasma concentrations. In previous studies, none of the investigated TKIs demonstrated a clinically meaningful response or significant improvement in therapy.7,9-12,31 All the TKIs that have been evaluated for ACC treatment, except linsitinib, are metabolized by CYP3A4, but the plasma levels were not monitored during the therapy.
Therefore, rapid metabolism resulting in insufficient drug exposure may contribute to the limited effectiveness of these drugs. It has been shown that the intake of rifampicin, a strong CYP3A4 inducer, increases CAB clearance by at least 4-fold and decreases the area under the curve by 77%.32 The intake of mitotane induces the expression of CYP3A4 as well,22 but it was discontinued before the initiation of therapy with CAB. Instead, therapy was administered with metyra- pone as an alternative treatment for Cushing syndrome.
Copyright @ 2021 Wolters Kluwer Health, Inc. All rights reserved.
Cabozantinib plasma concentration [ng/mL]
1000
500
8
0
0
50
100
150
200
250
0
5
10
15
20
25
A
Time since first dose [h]
B
Time since last dose [h]
C
Cmin,ss
Metyrapone acts as an inhibitor of CYP3A433 and induces the expression of this metabolizing enzyme via pregnane X receptor activation.34 Consequently, TKI clearance could not be estimated without drug monitoring.
Cabozantinib plasma concentration [ng/ml]
1250
1000
750
500
0
5
10
15
20
25
Time since last dose [h]
Copyright @ 2021 Wolters Kluwer Health, Inc. All rights reserved.
To date, there is no information on the influence of hemodialysis on the PKs of CAB. Filtration by hemodialysis may have increased clearance, but due to the plasma protein binding of 99.7%,35 enhanced elimination does not seem to be the main reason for the low plasma levels. For a patient under- going hemodialysis and receiving dabrafenib, a TKI with a comparable plasma protein binding, Park et al36 showed that elimination via dialysis only played a minor role. However, alterations in protein binding is frequently observed in patients with renal dysfunction arising from lower serum albumin con- centrations or the accumulation of endogenous and exogenous substances, resulting in drug displacement from plasma proteins. Decreased protein binding can lead to an increased volume of distribution. On the other hand, adsorption processes on filter material during hemodialysis and altered body fluid composition (eg, edema) may also increase the apparent volume of distribu- tion. With an individual estimate of more than 300 L, far above the typical value of the PK parameter, these phenomena may explain the observations in our case. The increased individual apparent clearance suggests that the potentially reduced bioavail- ability of the drug may have played a role.
Low TKI exposure in patients with advanced ACC is not unusual, and it may account for the poor results in previous clinical trials.13 In our case, 18-fluorodeoxyglucose positron emission tomography and computed tomography after 3 months of treatment showed decreased tracer uptake and tumor necrosis despite the lower-than-predicted CAB concentrations. However, the patient died from the disease 6 months later. Thus, adapted plasma levels may contribute to better clinical outcomes. Dose adaptation was not performed in our case as the dose-effect
relationships were not established for CAB and are the subject of current research. Nonetheless, the definition of target values for HGFR/VEGFR inhibitors for tumor therapy is under discussion. For example, the correlation between CAB exposure and progression-free survival was investigated by the United States Food and Drug Administration for the approval of CAB in advanced RCC. After the daily administration of 60-mg CAB, the median trough concentration was 1125 ng/mL. An additional simulated dose change led to a smaller reduction in tumor size, from 11.9% for 60 mg to 9.1% for 40 mg and 4.5% for 20 mg daily, as well as a worse objective response rate. After changing the CAB exposure to 67% and 33% of the primary value, the hazard ratio increased to 1.1 and 1.39, respectively.16 According to these data, the lower plasma levels, as observed in our case, can decrease the changes in successful therapy. The malignancy itself, renal impairment, or related supportive therapy may sig- nificantly affect the PK of CAB. In MTC, apparent clearance is approximately doubled in comparison to other malignancies.30 Because of the potential of DDI, which holds for several other TKIs, the monitoring of the plasma levels is imperative to the correct interpretation of the results of clinical phase II studies. Even if these results cannot be generalized, the importance of further systematic investigations on pathophysiological condi- tions, specific subpopulations, and DDIs influencing the PKs of CAB has been identified.
CONCLUSION
ACC is an orphan but aggressive disease with limited chemotherapeutic options. TKI may be a promising approach, but several questions, including those related to PKs, are still unanswered. Nevertheless, new therapies should be made available to patients with severe diseases on an individual basis. Therefore, an LC-MS/MS method for the TDM of CAB, which demonstrated short acquisition and preparation durations and satisfied the high throughput requirements for bioanalytical monitoring, was developed. The method was used to monitor CAB exposure in patients undergoing hemodialysis. The measured plasma concentrations were lower than expected, and higher doses of CAB would have been required to achieve the expected plasma concentrations according to our simulations. As a result, PK modeling and simulations were performed, showing pronounced individual variability in PK characteristics and significant deviation from population predicted values. These results encourage further investigations for subpopulation-specific CAB monitoring and the potential use of TDM in personalized ACC therapy.
ACKNOWLEDGMENTS
The authors acknowledge Nielka van Erp from Radboud University in Nijmegen, the Netherlands, for cross-validating the method. The authors also thank Sabine Kendl for her technical assistance. Support from the German Research Foundation was also acknowledged.
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