title: Sorafenib dose escalation is not uniformly associated with blood pressure elevations in normotensive patients with advanced malignancies.
abstract: Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: S
authors.initials: S
authors.lastname: Karovic
authors.affiliation: Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wen
authors.affiliation: 1] Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA [2] Department of Health Studies, The University of Chicago, Chicago, Illinois, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Karrison
authors.affiliation: 1] Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA [2] Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Bakris
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Levine
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: House
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wu
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: V
authors.initials: V
authors.lastname: Thomeas
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Wright
authors.affiliation: 1] Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA [2] Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: E E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: 1] Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA [2] Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA [3] Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: 1] Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA [2] Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA [3] Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: 1] Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA [2] Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA [3] Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Maitland
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011446:Prospective Studies; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor