Jianping Zhang
GlaxoSmithKline
Objectives: Eltrombopag is a non-peptide thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection to allow the initiation and maintenance of interferon-based antiviral therapy. It has been reported previously that eltrombopag exposure was influenced by the severity of liver disease [1]. The objective of the present analysis was to evaluate the impact of hepatic impairment on eltrombopag pharmacokinetics (PK) in thrombocytopenic patients with hepatic impairment using population PK modelling approach.
Methods: The population PK analysis involved 742 subjects from 6 studies, of which 28 were healthy subjects, 673 were patients with HCV, and 41 were patients with liver disease of other etiology. Of the 714 patients, 642 (90%) had mild hepatic impairment (Child-Pugh Score [CPS] 5-6), 67 (9%) had moderate hepatic impairment (CPS 7-9), and 2 (<1%) had severe hepatic impairment (CPS >9). Nonlinear mixed effects modelling was conducted using NONMEM VII. Influential covariates were evaluated using a semi-full model approach followed by backward elimination. Visual predictive check was implemented for final model evaluation.
Results: Consistent with what was reported previously [2], the eltrombopag PK was described by a linear two-compartment model with absorption lag time and dual sequential first-order absorption. Race (East+South East Asian vs. Others), gender, and severity of hepatic impairment were the primary predictors of eltrombopag CL/F, whereas Race (Central+South Asian vs. Others) and body weight were the predictors of eltrombopag Vc/F. Reduction of eltrombopag CL/F was found to be associated with the increased severity of hepatic impairment. CL/F in patients with CPS 5 was 49% lower than healthy subjects. CL/F in patients with CPS 6 was 64% lower than healthy subjects. As the severity of hepatic impairment further increased, less reduction in eltrombopag CL/F was found. For patients with CPS 8, CL/F was 69% lower than healthy subjects.
Conclusions: Population PK modelling of eltrombopag from multiple studies enabled robust quantification of the influence of hepatic impairment on eltrombopag pharmacokinetics, which further supported the eltrombopag dosing strategy in patients with greater degree of hepatic impairment.
References:
[1] Bauman JW, Vincent CT, Peng B, Wire MB, Williams DD, and Park JW. Effect of hepatic or renal impairment on eltrombopag pharmacokinetics. J Clin Pharmacol (2011) 51:739-50.
[2] Farrel C, Hayes S, Giannini E, Afdhal N, Tayyab G, Mohsin A, Lee JW, Han KH, Tanno H, Campbell F, Theodore D, Blackman N, Hyde D, and Zhang J. Gender, race, and severity of liver disease influence eltrombopag exposure in thrombocytopenic patients with chronic liver disease. Hepatology (2010) 52(S1):920A.
Reference: PAGE 23 (2014) Abstr 3028 [www.page-meeting.org/?abstract=3028]
Poster: Drug/Disease modeling - Absorption & PBPK