Population PK/PD Modeling of Eltrombopag in ITP Patients and Optimization of Response-Guided Dosing
Siobhan Hayes (1), Daniele Ouellet (2), Jianping Zhang (2), Mary Wire (2), Ekaterina Gibiansky (1)
(1) ICON Development Solutions, Ellicott City, MD, USA; (2) GlaxoSmithKline, Research Triangle Park, NC, USA
Background: Eltrombopag is the first oral, small molecule, non-peptide thrombopoietin receptor (TPO-R) agonist. It has been shown to induce differentiation of normal marrow progenitors and to increase platelet counts in pre-clinical and clinical studies1, 2. Eltrombopag is being developed for medical disorders associated with thrombocytopenia, and has been recently approved in the United States for treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP). The population pharmacokinetics of eltrombopag in ITP patients has been described previously (PAGE 18 (2009) Abstr 1502 [www.page-meeting.org/?abstract=1502]). The model identified weight, Asian race, concomitant use of corticosteroids, and gender as predictors of eltrombopag exposure.
Objectives: The population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to 1) characterize the relationship between plasma eltrombopag concentrations and platelet counts (PLTC) in patients with ITP, and 2) estimate PLTC response for different dosing regimens, subpopulations, and dose adjustment schemes guided by PLTC response (target PLTC >50 and <200 Gi/L).
Methods: Eighty eight patients who received 30, 50 or 75 mg of eltrombopag once-daily (QD) for 6 weeks and 67 patients who received placebo contributed 627 and 590 platelet measurements, respectively. A life-span3 PK/PD model composed of a precursor production compartment, maturation compartments, and a blood platelet compartment was implemented in NONMEM. Individual plasma eltrombopag concentrations, computed from the population PK model, increased the production rate of platelet precursors. A mixture model was introduced to account for non-responders. Demographics, use of corticosteroids, prior use of ITP medications, splenectomy, and thrombopoietin concentration were explored as potential covariates. A posterior predictive check was used to evaluate the model. Extensive simulations were performed to understand the impact of age, gender, race, baseline PLTC, corticosteroid use, and responder vs. non-responder following 10 weeks of QD dosing of 50 mg eltrombopag. Additional simulations were carried out to determine the impact of dose reductions to 25 mg QD/25 mg QOD/12.5 mg QD if PLTC >200 Gi/L or dose increases to 75 mg QD if PLTC <50 Gi/L following at least 2 weeks of dosing.
Results: The final model consisted of 7 compartments (3 PK, 1 precursor, 2 maturation, and 1 circulation). The zero-order production rate (KIN) and the first-order maturation rate of platelet precursors (KT) were fixed to the values previously estimated in healthy subjects (KIN=1.43 Gi/L/hr, KT=0.0253 hr-1, CVKT=75.7%). The first-order platelet degradation rate (KDEG) was inversely proportional to baseline PLTC. In responders (estimated as 81% of patients), KIN increased linearly with eltrombopag concentration (SLOP=0.579 mL/mg, CV=89.7%). Eltrombopag did not increase platelet production (SLOP=0) in non-responders. Females and older patients were more sensitive to eltrombopag, with higher SLOP estimates compared to males (2.42-fold, 95%CI=1.15-3.69) and younger patients (power coefficient 1.27, 95%CI=0.525-2.01 for AGE/50).
Simulations of PLTC over time following different dosing regimens predicted higher PLTC for the following subpopulations (in descending order): Asian race, age ³65 years, baseline PLTC >15 Gi/L, female, and concurrent corticosteroid use due to either higher eltrombopag exposure or greater PD response. Simulations supported 50 mg QD as an appropriate starting regimen, with biweekly individual dose adjustment to titrate each patient's dose until a target platelet response is achieved. Following dose decrease (to 25 mg QD), PLTC of 60% of patients who exceeded the upper target level (PLTC > 200 Gi/L) were predicted to decrease to below that level. Following dose increase (to 75 mg QD), 29% of patients who did not respond initially (PLTC < 50 Gi/L) were predicted to respond.
Conclusions: The developed PK/PD model was prospectively predictive of platelet response in different subpopulations and of the impact of dose adjustment on PLTC. Simulations based on the model identified dose adjustment regimens that minimized the risk of high PLTC and maximized the patient's chance to respond to treatment.
References:
1. Bussel J. et al. Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic Purpura. N Engl J Med 2007.
2. Bussel J et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009.
3. Friberg L. et al. Semiphysiological Model for the Time Course of Leukocytes after Varying Schedules of 5-Fluorouracil in Rats, JPET, 2000.
