Bettina Friedl (1), Max Kurlbaum (2,3), Maria-Elisabeth Goebeler (4), Martin Fassnacht (3,4), Matthias Kroiss (3,4), Oliver Scherf-Clavel (1)
(1) University of Würzburg, Institute for Pharmacy and Food Chemistry, Würzburg, Germany, (2) University Hospital Würzburg, Central Laboratory, Clinical Chemistry and Laboratory Medicine, Würzburg, Germany, (3) University Hospital Würzburg, Department of Internal Medicine I, Division of Endocrinology and Diabetology and Core Unit Clinical Mass Spectrometry, Würzburg, Germany, (4) University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany
Introduction: Adrenocortical carcinoma (ACC) is a rare but highly aggressive disease with few treatment options [1]. The current standard of care in advanced ACC is the combination of etoposide, doxorubicin and cisplatin with mitotane (EDP-M) with an objective response rate of only 23% [2]. New treatment options are urgently needed and based on positive case reports the oral multi-kinase inhibitor Cabozantinib (CAB) is currently subject of a single centre, phase II study to evaluate its safety and efficacy in advanced ACC [3]. As it is the first study of CAB in this patient population there is little experience so far and physiologically based pharmacokinetic (PBPK) modelling was applied to develop a PBPK model of CAB and thereby to get a better understanding of the pharmacokinetic behaviour of CAB in ACC patients.
Objectives:
- To develop a whole-body PBPK model of Cabozantinib after oral administration in healthy volunteers and to evaluate its application in patients with adrenocortical carcinoma
Methods: A PBPK model of CAB following oral administration was developed using a combined bottom-up and top-down strategy. The development of the PBPK model was performed using PK-Sim® (Version 8) as part of the Open Systems Pharmacology Suite [4]. Information about drug-dependent properties were extracted from published literature. For initial model development, plasma concentration-time profiles from healthy volunteers (HV) following a single oral dose of 20 mg, 40 mg or 60 mg were used and when necessary parameters were estimated to adequately describe the data. Single dose simulations were transmitted to steady-state conditions (60 mg once daily) which is possible due to linear pharmacokinetics of CAB. A virtual ACC population was created based on the demographic data from 45 ACC patients who presented at the University Hospital Würzburg during the last years. Model simulations for HV were compared to simulations for typical ACC patients and the model was evaluated with concentration-time data obtained from seven ACC patients treated at the University Hospital Würzburg.
Results: As CAB itself is not found in urine [5] but is extensively metabolized via CYP3A4 [6], this is the only route of elimination used in the model. Michaelis-Menten constant KM was fitted based on the plasma concentration-time data to 0.97 µM and the catalytic rate constant kcat was fitted to 1.05 min-1. A Weibull function (time (50%): 17.7 min, lag time: 5.4 min, shape: 5.6) was used to quantify dissolution of the CAB tablet (Cabometyx®). The developed model was able to precisely describe the observed plasma concentrations following a single dose of 60 mg with a mean Cmax ratio (Cmax predicted / Cmax observed) of 1.0, a mean tmax ratio (tmax predicted / tmax observed) of 0.81 and a mean area under the curve (AUC) ratio (AUC predicted / AUC observed) of 0.95. Transmitting from single to multiple dose simulation was successful in terms of profile shape and PK parameters and resulted for example in a 3.8 fold higher Cmax, which is comparable with literature values [6]. Simulations for a typical male and female ACC population showed a twofold lower plasma exposure compared to HV, which is consistent with our clinical observations. By changing the dosage from 60 mg once daily to 65 mg twice daily in ACC patients, it was possible to simulate CAB steady state plasma concentrations similar to steady state plasma concentrations in HV.
Conclusions: Standard dosage of 60 mg daily is not sufficient in ACC patients to achieve the same CAB plasma concentrations as in HV. ACC patients receiving CAB show significantly lower plasma concentrations compared to HV. By integrating mean demographic characteristics of ACC patients into the HV model, the observed data are much better described but CAB concentration is still overestimated. Thus, there may be additional processes in ACC patients leading to lower plasma concentrations, which should be investigated next.
References:
[1] Fassnacht M et al. Update in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(12):4551-64.
[2] Kroiss M et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97(10):3495-503.
[3] ClinicalTrials.gov Identifier: NCT03612232: Cabozantinib in Advanced Adrenocortical Carcinoma.
[4] Eissing T et al. A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks. Front Physiol. 2011;24(2):4
[5] Lacy SA et al. Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib. Clin Pharmacokinet. 2017;56(5):477-91.
[6] Nguyen L et al. Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. J Clin Pharmacol. 2015;55(9):1012-23.
Reference: PAGE () Abstr 9290 [www.page-meeting.org/?abstract=9290]
Poster: Drug/Disease Modelling - Absorption & PBPK