Population Pharmacokinetics of Eltrombopag in Healthy Subjects and Patients With Chronic Idiopathic Thrombocytopenic Purpura

Abstract

The population pharmacokinetics of eltrombopag were characterized in healthy subjects (n = 111) and patients with idiopathic thrombocytopenic purpura (ITP) (n = 88) using nonlinear mixed-effects modeling. The final model was evaluated via graphical diagnostics and through predictive check and nonparametric bootstrap procedures. A 2-compartment model with dual sequential first-order absorption, absorption lag time, and interoccasion variability in absorption adequately described the data. For a typical 70-kg Caucasian male ITP patient not taking corticosteroids, estimated parameters were apparent clearance (CL/F) = 0.668 L/h, apparent volume of the central compartment (Vc/F) = 8.76 L, apparent volume of the peripheral compartment (Vp/F) = 11.3 L, and distributional clearance (Q/F) = 0.399 L/h. Eltrombopag CL/F, Vc/F, Q/F, and Vp/F increased with body weight. For the range of weights included (43-122 kg), the parameters ranged from 26% lower to 41% higher than for a 70-kg individual. The typical eltrombopag CL/F was 33% lower in East Asians compared with other races, 26% lower in patients taking corticosteroids concomitantly, 19% lower in females compared with males, and 17% higher in healthy subjects compared with ITP patients. There was also a dose effect, with CL/F and Vc/F estimated to be respectively 68% and 55% higher for doses 20 mg or less. In conclusion, East Asian race had the largest impact on eltrombopag exposure with a lower initial dose being recommended.

Population pharmacokinetic/pharmacodynamic modelling of eltrombopag in healthy volunteers and subjects with chronic liver disease

“…This absorption model was also assessed for the present CLD analysis but did not improve the fit compared with the sequential dual first-order absorption. The estimated typical (95% CI) PK parameter values for the reference White male healthy volunteer population were comparable to previously reported values [9].…”

“…The population PK/PD model was developed from patients with CLD (n = 79) for whom the PD data were modelled using the post hoc PK parameter estimates for each patient from the final population PK model (accounting for significant covariates) to predict the eltrombopag concentrations. The previously published eltrombopag PK and PK/PD models for healthy volunteers, ITP patients and patients with HCV were the starting points for the present analyses [9][10][11].…”

“…Investigation of covariate-parameter relationships was based on the range of covariate values in the data set, scientific interest, mechanistic plausibility, exploratory graphics and previously reported covariateparameter relationships for eltrombopag PK and PK/PD in other patient populations, such as female sex and East Asian race, which have been reported as significant predictors of eltrombopag PK in healthy subjects and patients with ITP [9]. A full model approach was implemented, where all covariate-parameter relationships of interest were entered in the model, and parameters were estimated.…”

“…The population pharmacokinetics (PK) and PK/ pharmacodynamics (PK/PD) of eltrombopag have been described previously for patients with immune thrombocytopenic purpura (ITP) [9,10] and for subjects with hepatitis C (HCV) [11]. The aim of this analysis was to build a population PK/PD model to characterize the relationship between plasma eltrombopag concentrations and platelet count in CLD patients to understand determinants of the response.…”

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

“…Various types of such anionic therapeutic agents are taken up by hepatic uptake transporters, and both OATP1B1 and OATP1B3 play important roles in their hepatic disposition (Kalliokoski et al, 2010;Watanabe et al, 2010). Nevertheless, ELT has been thought to be a nonsubstrate of OATP1B1 (Gibiansky et al, 2010). On the other hand, ELT was found to be a substrate of OATP1B1 in the present study, because the uptake of ELT by HEK293/PDZK1 cells transfected with OATP1B1 was higher than that in vector-transfected cells (Fig.…”