Kai Wu (1), Mita Thapar1 (2*), Colm Farrell2 (2), Siobhan Hayes3 (2), Haiyi Guo (3), Ming Hou (4), Jianping Zhang (5)
(1) Department of Clinical Pharmacology, Modeling & Simulation, GlaxoSmithKline, Shanghai, China, (2) ICON Early Phase Services, Marlow, Buckinghamshire, UK, (3) China Medicine Development, GlaxoSmithKline, Shanghai, China, (4) Department of Hematology, Qilu Hospital, Shandong University, Shandong, China, (5) Department of Clinical Pharmacology, Modeling & Simulation, GlaxoSmithKline, Research Triangle Park, NC, USA, (*) Presenting author
Objectives: The objectives were to characterize the population pharmacokinetics (Pop-PK) and pharmacokinetics/pharmacodynamics (Pop-PK/PD) of eltrombopag and to evaluate platelet count (PLTC) response following different eltrombopag regimens through simulations in Chinese adult patients with chronic primary immune thrombocytopenia (cITP).
Methods: NONMEM® program version VII level 3.0 was used for the Pop-PK and Pop-PK/PD analyses (ICON, Ellicott City, Maryland, USA). PDx-Pop® (Version 5.1) was used as a NONMEM interface. S-Plus (TIBCO Spotfire S+® 8.2 for Windows) was used for plotting and analyzing NONMEM outputs. Model-based simulations were then performed to predict PLTC response.
Results: The Pop-PK of eltrombopag was described by a 2-compartment model with first-order absorption and elimination and absorption lag-time. The steady state exposure in Chinese patients was approximately 55% higher than the non-East Asian patients. The Pop-PK/PD of eltrombopag was described by a 4 transit compartments model where the increase in platelet production rate was linearly related to the plasma eltrombopag concentration. Only 11% of patients were identified as non-responders to eltrombopag. Simulations showed that about 70-80% steady state PLTC response was achieved at Week 2, and the proportion of patients achieving a PLTC of 50-150 x 109/L was comparable between Week 2 and 6 following 12.5, 25, 50, and 75 mg once daily (QD) dosing. 25 mg QD had a more balanced response than 12.5, 50, and 75 mg QD in efficacy (proportion of patients with a PLTC of 50-150 x 109/L, 27% vs 20, 30, and 30%) and the risk of thrombocytosis (proportion of patients with a PLTC >250 x 109/L, 4% vs 1, 10 and 16%). Simulations of PLTCs following the dose titration regimen showed that ≥ 42% of patients achieved a PLTC of 50-150 x 109/L at Week 6 or later, compared to ≤30% when 12.5, 25, 50, and 75 mg fixed QD doses were given. Only ≤5% of the patients had a PLTC >250 x 109/L throughout 24 weeks of treatment, compared to 3, 7, 16 and 24% when the fixed QD doses of eltrombopag were given, respectively.
Conclusion: The pop-PK and PK/PD of eltrombopag in Chinese cITP patients were adequately characterized in the current analyses and were consistent with the similar analysis done in other cITP populations. The modeling and simulation results support the eltrombopag dose titration regimen with 25 mg QD as a starting dose and a 2-week titration interval in Chinese cITP patients.
Reference: PAGE 24 (2015) Abstr 3322 [www.page-meeting.org/?abstract=3322]
Poster: Drug/Disease modeling - Other topics