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.
Subject(s)
Blood Pressure/drug effects , Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Adult , Aged , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasms/pathology , Neoplasms/physiopathology , Niacinamide/administration & dosage , Niacinamide/pharmacokinetics , Phenylurea Compounds/pharmacokinetics , Prospective Studies , Sorafenib , Young AdultABSTRACT
Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis-Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e17; doi:10.1038/psp.2012.18; advance online publication 5 December 2012.
ABSTRACT
A sensitive assay was developed for the quantitation of 5-fluorouracil (5-FU) and uracil using liquid-liquid extraction (LLE) and HPLC with UV detection. Analyses were performed with four microBondapak C18 columns connected in series using 20 mM acetic acid with 1% ACN as mobile phase. The calibration curves were linear across the range of 26-1000 ng ml(-1) (0.21-7.8 microM) for 5-FU and 1.0-14.0 microg ml(-1) (0.01-110 microM) for uracil. This assay has been implemented to determine the plasma concentrations for pharmacokinetic studies for 5-FU and uracil in conjunction with clinical trials.
