Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data
Journal Title: The AAPS Journal - Year 2009, Vol 11, Issue 2
Abstract
The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlusTM (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration–time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs’ bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.
Authors and Affiliations
Viera Lukacova, Walter S. Woltosz, Michael B. Bolger
Keywords
Related Articles
- EP ID EP681464
- DOI 10.1208/s12248-009-9107-2
- Views 88
- Downloads 0
Next Generation Ligand Binding Assays—Review of Emerging Real-Time Measurement Technologies
Over the last few years, numerous ligand binding assay technologies that utilize real-time measurement have been introduced; however, an assemblage and evaluation of these technologies has not previously been published....
Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications
Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocy...
G.L. Amidon, H. Lennernas, V.P. Shah, and J.R. Crison. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res 12, 413–420, 1995—Backstory of BCS
The Biopharmaceutics Classification System (BCS) has become widely accepted today in the academic, industrial, and regulatory world. While the initial application of the BCS was to regulatory science bioequivalence (BE)...
A Neutralizing Antibody Assay Based on a Reporter of Antibody-Dependent Cell-Mediated Cytotoxicity
Benralizumab is a humanized anti-IL5 receptor α (IL5Rα) monoclonal antibody (mAb) with enhanced (afucosylation) antibody-dependent cell-mediated cytotoxicity (ADCC) function. An ADCC reporter cell-based n...
Polymer-drug conjugates as modulators of cellular apoptosis
The successful clinical application of polymer-protein conjugates (PE Gylated enzymes and cytokines) and the promising results arising from clinical trials with polymerbound chemotherapy (eg, doxorubicin or paclitaxel) h...