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, VEGF-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.
Lindauer
A
A
Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany.
Di Gion
P
P
Kanefendt
F
F
Tomalik-Scharte
D
D
Kinzig
M
M
Rodamer
M
M
Dodos
F
F
Sörgel
F
F
Fuhr
U
U
Jaehde
U
U
D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077210:Sunitinib; D013997:Time Factors
D015415:Biomarkers; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib