Population Pharmacokinetics of Telapristone (CDB-4124) and its Active Monodemethylated Metabolite CDB-4453, with a Mixture Model for Total Clearance
Journal Title: The AAPS Journal - Year 2011, Vol 13, Issue 4
Abstract
Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h−1. Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmetest) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.
Authors and Affiliations
Denise Morris, Joseph Podolski, Alan Kirsch, Ronald Wiehle, Lawrence Fleckenstein
Keywords
Related Articles
- EP ID EP681347
- DOI 10.1208/s12248-011-9304-7
- Views 63
- Downloads 0
Pre-Existing Biotherapeutic-Reactive Antibodies: Survey Results Within the American Association of Pharmaceutical Scientists
The immunogenicity profile of a biotherapeutic is determined by a multitude of product and patient-related risk factors that can influence the observed incidence and clinical consequences of immunogenicity. Pre-existing...
Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation
Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) a...
A Novel Ultrasensitive Hybridization-Based ELISA Method for 2-Methoxyphosphorothiolate MicroRNAs and Its In vitro and In vivo Application
MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that bind to target mRNAs and regulate their expression. Recent evidence has indicated the involvement of miRNAs in human malignancies. It has been suggested that...
Skin oxygenation after topical application of liposome-entrapped benzyl nicotinate as measured by EPR oximetry in vivo: Influence of composition and size
New and improved drug delivery systems are the important subject of much scientific research. The development of formulations that increase skin oxygenation and of methods for measuring oxygen levels in skin are importan...
Independence of substituent contributions to the transport of small-molecule permeants in lipid bilayer
Purpose: To explore the independence of functional group contributions to permeability of nonelectrolytes across egg lecithin bilayers. Methods. The transport rates were measured of a series of α-substituted p-me...