Pharmacokinetic-Pharmacodynamic Modeling of the Angiogenic Factors VEGF, sVEGFR-2, sVEGFR-3 and sKIT following Sunitinib Treatment in GIST
Emma K. Hansson(1), Brett Houk(2), Michael Amantea(2), Peter Milligan(2), Mats O. Karlsson(1), Lena E. Friberg(1)
(1)Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Pfizer Global Research and Development
Objectives: An identified relationship between suitable biomarkers and tumor response could potentially improve measures of treatment activity and facilitate treatment individualization for anti-angiogenic drugs both during drug development and in clinical practice. The aim of the present study was to investigate dose-exposure-biomarker relationships following Sutent® (sunitinib) treatment with focus on the potential biomarkers VEGF, sVEGFR-2, sVEGFR-3 and sKIT.
Methods: Data on the four angiogenic factors following up to 85 weeks of treatment with the oral tyrosine kinase inhibitor sunitinib and/or placebo in 303 patients with gastro-intestinal stromal tumors (GIST) were available. The sunitinib PK was described using individual PK parameters [1] and indirect response models [2] were fitted to the log transformed biomarker data using the FOCE method with INTERACTION in NONMEM VI. Symptomatic and protective disease progression models were evaluated to describe biomarker modulations due to natural history of the disease.
Results: The dose-exposure-biomarkers relationships were adequately described using indirect response models where sunitinib treatment decreased the production of sVEGFR-2, sVEGFR-3 and sKIT and inhibited the degradation of VEGF. A linear symptomatic disease progression model with a common slope described the increase of VEGF and sKIT over time in the absence of drug. The estimated mean residence time for the different biomarkers were 4 (VEGF), 23 (sVEGFR-2), 17 (sVEGFR-3) and 101 (sKIT) days. A common typical IC50 parameter for the four biomarkers could be estimated and the individual parameters for VEGF, sVEGFR-2 and sVEGFR-3 were highly correlated.
Conclusions: : The time-courses of the angiogenic factors VEGF, sVEGFR-2, sVEGFR-3 and sKIT following placebo and sunitinib treatment were well characterized. The high within-patient correlations in IC50 indicate that it may be sufficient to measure a limited set of the angiogenic factors for exploring correlations of treatment outcome.
References:
[1] Amantea MA., et al., J Clin Oncol 26: 2008 (May 20 suppl; abstr 2522)
[2] Dayneka N., et al., JPB 21 ; 21: 1457-78, 1993
