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 92
- Downloads 0
Influence of fluoxetine on olanzapine pharmacokinetics
Conventional antidepressant treatment fails for up to 30% of patients with major depression. When there are concomitant psychotic symptoms, response rates are even worse. Thus, subsequent treatment often includes combina...
Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases
With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current ther...
Prediction of Exposure–Response Relationships to Support First-in-Human Study Design
In drug development, phase 1 first-in-human studies represent a major milestone as the drug moves from preclinical discovery to clinical development activities. The safety of human subjects is paramount to the conduct of...
Solid Lipid Budesonide Microparticles for Controlled Release Inhalation Therapy
A solid lipid microparticle system containing budesonide was prepared by oil in water emulsification followed by spray drying. The solid lipid system was studied in terms of morphology, particle size distribution, crysta...
Fetal Microchimerism in Cancer Protection and Promotion: Current Understanding in Dogs and the Implications for Human Health
Fetal microchimerism is the co-existence of small numbers of cells from genetically distinct individuals living within a mother’s body following pregnancy. During pregnancy, bi-directional exchange of cells occur...