Date of Degree
PhD (Doctor of Philosophy)
Lawrence L. Fleckenstein
First Committee Member
Lee E Kirsch
Second Committee Member
Daryl J Murry
Third Committee Member
Erika J Ernst
Fourth Committee Member
Rhonda R DeCook
In this thesis, the population pharmacokinetics of telapristone and its active metabolite, CDB-4453 was evaluated using nonlinear mixed effects modeling (NONMEM®). A two-compartment (parent) one compartment (metabolite) mixture model with first order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453.
For the Phase I/II pharmacokinetic analysis (effect of renal and hepatic impairment), 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. Population estimates for oral clearance (CL/F) for the high and low clearance groups were 11.6 L/h and 3.34 L/h, respectively. Twenty-five percent of the subjects were 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 and apparent clearance of the metabolite (CLM/F) was 2.43 L/h.
For the pharmacokinetic analysis evaluating the effect of food; food decreased the Ka of telapristone (Ka for the fed and fasted state was 0.467 and 5.06 h-1, respectively). Population estimates of the high and low CL/F groups were 12.0 L/h and 3.15 L/h, respectively. Thirty-one percent of the subjects were allocated to the high clearance group. V2/F, Q/F and V/4 and Fmetest were 52.8 L, 7.53 L/h, 84.8 L and 0.193/L, respectively. CLM/F was 2.10 L/h.
An external validation was performed using the final parameter estimates from the pooled pharmacokinetic analysis (effect of renal and hepatic impairment and the effect of food). From this pharmacokinetic analysis, Ka for the fed and fasted state was 0.299 and 2.35 h-1, respectively. Population estimates for the high and low CL/F groups were 11.6 L/h and 3.22 L/h, respectively. The percentage of subjects allocated to the high clearance group was 29%. V2/F, Q/F, V/4 and Fmetest were 52.8 L, 11.6 L/h and 93.8 L and 0.186/L, respectively. CLM/F was 2.23 L/h. The final model did not meet the requirement for adequate predictability using the external validation dataset. However, the external validation dataset only included samples with limited early time points. Because of the limited sampling times, it is difficult to make a conclusion about the overall adequacy of the model. An external validation dataset with more extensive sampling will be needed in order to better assess the predictability final model.
This is the first comprehensive review of the pharmacokinetics of telapristone and CDB-4453.
Mixture Modeling, NONMEM, Parent-metabolite, Population Pharmacokinetics
xviii, 187 pages
Includes bibliographical references (pages 180-187).
Copyright 2011 Denise Nichole Morris
Morris, Denise Nichole. "Population pharmacokinetics of telapristone and its active metabolite CDB-4453." PhD (Doctor of Philosophy) thesis, University of Iowa, 2011.