14 research outputs found
The use of a physiologically based pharmacokinetic model to evaluate deconvolution measurements of systemic absorption
BACKGROUND: An unknown input function can be determined by deconvolution using the systemic bolus input function (r) determined using an experimental input of duration ranging from a few seconds to many minutes. The quantitative relation between the duration of the input and the accuracy of r is unknown. Although a large number of deconvolution procedures have been described, these routines are not available in a convenient software package. METHODS: Four deconvolution methods are implemented in a new, user-friendly software program (PKQuest, ). Three of these methods are characterized by input parameters that are adjusted by the user to provide the "best" fit. A new approach is used to determine these parameters, based on the assumption that the input can be approximated by a gamma distribution. Deconvolution methodologies are evaluated using data generated from a physiologically based pharmacokinetic model (PBPK). RESULTS AND CONCLUSIONS: The 11-compartment PBPK model is accurately described by either a 2 or 3-exponential function, depending on whether or not there is significant tissue binding. For an accurate estimate of r the first venous sample should be at or before the end of the constant infusion and a long (10 minute) constant infusion is preferable to a bolus injection. For noisy data, a gamma distribution deconvolution provides the best result if the input has the form of a gamma distribution. For other input functions, good results are obtained using deconvolution methods based on modeling the input with either a B-spline or uniform dense set of time points
PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol
BACKGROUND: A "physiologically based pharmacokinetic" (PBPK) approach uses a realistic model of the animal to describe the pharmacokinetics. Previous PBPKs have been designed for specific solutes, required specification of a large number of parameters and have not been designed for general use. METHODS: This new PBPK program (PKQuest) includes a "Standardhuman" and "Standardrat" data set so that the user input is minimized. It has a simple user interface, graphical output and many new features: 1) An option that uses the measured plasma concentrations to solve for the time course of the gastrointestinal, intramuscular, intraperotineal or skin absorption and systemic availability of a drug – for a general non-linear system. 2) Capillary permeability limitation defined in terms of the permeability-surface area products. 4) Saturable plasma and tissue protein binding. 5) A lung model that includes perfusion-ventilation mismatch. 6) A general optimization routine using either a global (simulated annealing) or local (Powell) minimization applicable to all model parameters. RESULTS: PKQuest was applied to measurements of human propranolol pharmacokinetics and intestinal absorption. A meal has two effects: 1) increases portal blood flow by 50%; and 2) decreases liver metabolism by 20%. There is a significant delay in the oval propranolol absorption in fasting subjects that is absent in fed subjects. The oral absorption of the long acting form of propranolol continues for a period of more than 24 hours. CONCLUSIONS: PKQuest provides a new general purpose, easy to use, freely distributed and physiologically rigorous PBPK software routine
A Phase II trial of axitinib in patients with various histologic subtypes of advanced thyroid cancer: long-term outcomes and pharmacokinetic/pharmacodynamic analyses.
PurposeAxitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, has shown activity in advanced thyroid cancer in a Phase II study. We report updated overall survival and pharmacokinetic/pharmacodynamic (PK/PD) analyses from the study.MethodsPatients (N = 60) with advanced thyroid cancer of any histology for whom iodine-131 ((131)I) failed to control the disease or (131)I was not appropriate therapy were administered axitinib 5 mg twice daily. Objective response rate (primary endpoint), duration of response, progression-free survival, overall survival, safety, and PK/PD relationships were assessed.ResultsObjective response rate was 38 % [23 partial responses; 95 % confidence interval (CI) 26-52], and 18 (30 %) patients had stable disease lasting ≥16 weeks. Responses occurred in all histologic subtypes. With median follow-up of 34 months (95 % CI 32-37), median overall survival was 35 months (95 % CI 19-not estimable), median progression-free survival was 15 months (95 % CI 10-20), and median duration of response was 21 months (95 % CI 13-46). Most common Grade 3/4 treatment-related adverse events included hypertension (13 %), proteinuria (8 %), diarrhea (7 %), weight decrease (7 %), and fatigue (5 %). PK/PD analyses revealed trends toward greater tumor size reduction and response probability with higher axitinib plasma exposures.ConclusionsAxitinib appears active and well tolerated in patients with various histologic subtypes of advanced thyroid cancer, demonstrating durable responses and long overall survival. Axitinib may be useful for the treatment of advanced thyroid cancer