Ekaterina Gibiansky (1), Jianping Zhang (2), Daphne Williams (3), Zhao Wang (1), Daniele Ouellet (2)
(1) ICON Development Solutions, Ellicott City, MD, USA; (2) GlaxoSmithKline, Research Triangle Park, NC, USA; (3) Bristol-Myers Squibb, Princeton, NJ, USA
Objectives: Eltrombopag is an orally bioavailable small molecule agonist of thrombopoietin receptor (TPO-R) that has been recently approved for treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP). The aim of this analysis was to develop a population pharmacokinetic (PK) model of eltrombopag, predict steady-state exposure at therapeutic doses, and identify and quantify main demographic/covariate factors influencing eltrombopag exposure.
Methods: 111 subjects from 3 Phase 1 studies (dense data) and 88 patients from a Phase 2/3 study (sparse data) contributed 4093 plasma eltrombopag concentrations. Dosing in the studies ranged from 5 to 200 mg QD as a single dose, or as multiple doses administered for 5 days to 6 weeks duration. The analysis was performed using a mixed-effects modeling approach with the first-order conditional method (FOCEI) of NONMEM. The full model approach was implemented for covariate modeling, followed by elimination of insignificant or poorly estimated covariates. Visual predictive check and non-parametric bootstrap stratified by major covariates were implemented for model evaluation. Estimates of individual eltrombopag steady-state exposure were obtained by simulations and summarized for subpopulations identified by the model.
Results: PK of eltrombopag was described by a 2‑compartment linear model with dual sequential first-order absorption, absorption lag-time, and inter-occasion variability in absorption. Mean (95% CI) parameters of a typical 70 kg Caucasian male ITP patient not taking corticosteroids were estimated as CL/F=0.668 (0.561, 0.775) L/hr, Vc/F=8.76 (8.14, 9.38) L, Vp/F=11.3 (10.1, 12.5) L, and Q/F=0.399 (0.361, 0.437) L/hr. Inter-individual variability was 40.6%, and 37.4% in CL/F and V/F, respectively, with correlation of R=0.743. Inter-occasion variability in Ka (CV=127%) was much higher than inter-individual variability, which was therefore dropped from the model. In the ITP patients that received 50 mg QD dosing, mean (95% CI for the mean) steady-state exposure was estimated as AUCτ=108 µg*hr/mL (88, 134) and Cmax=8.01 (6.73-9.53) µg/mL. Weight increased CL/F, Vc/F, Q/F, and Vp/F equally with a power coefficient of 0.62 ((0.45-0.78) for CL/F and Q/F, and (0.25-0.98) for Vc/F, and Vp/F). For the range of weights in the analysis (43 to 122 kg), CL/F, Vc/F, Q/F, and Vp/F increased with body weight from 26% lower to 41% higher values than for 70-kg individual. The mean (95%CI) CL/F was 33% (26%, 41%) lower in Asians compared to other races, 26% (7%, 45%) lower in patients taking corticosteroids concomitantly, 19% (7%, 31%) lower in females compared to males; and 17% (0, 34%) higher in healthy subjects compared to ITP patients. Age and mild renal impairment did not influence the eltrombopag PK.
Conclusions: The developed population pharmacokinetic model identified and quantified patient characteristics predictive of eltrombopag exposure, and enabled further analysis to characterize pharmacokinetic-pharmacodynamic relationships.
Reference: PAGE 18 (2009) Abstr 1502 [www.page-meeting.org/?abstract=1502]
Poster: Applications- Coagulation