Pharmacokinetic/Pharmacodynamic Modeling of Sunitinib in Healthy Volunteers
Andreas Lindauer (1), Friederike Kanefendt (1), Cathleen Krambeer (1), Paola di Gion (2), Martina Kinzig (3), Fritz Sörgel (3), Uwe Fuhr (2), Ulrich Jaehde (1)
(1) Dept. of Clinical Pharmacy, University of Bonn, Germany; (2) Dept. of Pharmacology, University of Cologne, Cologne, Germany; (3) IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany
Objectives: Sunitinib is a novel tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and gastrointestinal stroma tumor [1]. It was shown that sunitinib influences blood pressure (BP) as well as plasma concentrations of various proteins (VEGF-A, VEGF-C, soluble VEGFR-2 and VEGFR-3) linked to its antiangiogenic properties [2]. We have conducted an explorative study in healthy subjects to investigate the influence of sunitinib on the time course of these biomarkers. PK/PD models were developed to describe the concentration-effect relationship.
Subjects and Methods: 50 mg sunitinib were orally administered to 12 healthy subjects on 3 or 5 consecutive days. Blood samples were drawn frequently. Plasma concentrations of sunitinib and its major metabolite (SU12662) were determined by LC-MS/MS. Concentrations of circulating biomarkers were measured by immunoassays. A sequential PK/PD analysis was performed using NONMEM 6.2. One thousand patients were simulated with the final models to predict the biomarker response after 28 days of sunitinib treatment (50 mg qd).
Results: The PK of sunitinib and SU12662 could be adequately described with a multi-compartment model accounting for systemic and pre-systemic formation of the metabolite and resulted in parameter estimates similar to published data [3]. The rapid rise of systolic and diastolic BP after sunitinib administration was described with an immediate effect (Emax) model. Decreasing concentrations of sVEGFR-2 were modeled using an indirect response model assuming that sunitinib inhibits the production of this protein.
Simulations showed a median (90% PI) change of sVEGFR-2 levels relative to baseline of 0.62 (0.39-0.92). In 15.3% of the simulated patients diastolic BP increased more than 20 mmHg.
No concentration dependent changes of VEGF-C levels were observed in this study. Analyses of VEGF-A and sVEGFR-3 levels are ongoing at present.
Conclusions: Biomarker response to sunitinib exposure also occurs independent of effects on a tumor in healthy volunteers even in a short period. The time course of the effect could be successfully described with PK/PD models. Simulations are consistent with clinical observations in cancer patients [1;2]. The approach of modeling biomarker data obtained from healthy volunteers may also be applicable to other VEGFR tyrosine kinase inhibitors and could support the drug development process at an early stage.
Acknowledgements: This investigation is supported by the Central European Society for Anticancer Drug Research (CESAR).
References:
[1] Rini BI. Sunitinib. Expert Opin Pharmacother 2007; 8:2359-2369.
[2] Deprimo S, Bello C, Smeraglia J, Baum C, Spinella D, Rini B et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 2007; 5:32.
[3] Houk BE, Bello CL, Kang D, Amantea M. A Population Pharmacokinetic Meta-analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients. Clin Cancer Res 2009; 15:2497-2506.