ABSTRACT
Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting nonuniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastrointestinal patients, the time-courses of liver metastases' maximum transaxial diameters, software-calculated actual volumes (Vactual ) and calculated ellipsoidal volumes were characterized by logistic growth models, in which imatinib induced a linear dose-dependent size reduction. An indirect response model best described the reduction in density. Substantial interindividual variability in the drug effect of all response assessments and additional interlesion variability in the drug effect on density were identified. The predictive ability of longitudinal tumor unidimensional and three-dimensional size and density on overall survival (OS) and progression-free survival (PFS) were compared using parametric time-to-event models. Death hazard increased with increasing Vactual . This framework may guide early clinical interventions based on three-dimensional tumor responses to enhance benefits for patients with gastrointestinal stromal tumors (GIST).
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Stromal Tumors , Imatinib Mesylate/therapeutic use , Liver Neoplasms , Models, Biological , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/pathology , Humans , Kaplan-Meier Estimate , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Male , Middle Aged , Tomography, X-Ray Computed , Treatment Outcome , Tumor BurdenABSTRACT
The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-ß-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.