Pharmacokinetic/Pharmacodynamic Modeling of Biomarker Response to Sunitinib in Healthy Volunteers

A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEG F-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.