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Population PK/PD Modeling of Eltrombopag in Healthy Volunteers and Patients With Immune Thrombocytopenic Purpura and Optimization of Response‐Guided Dosing
Author(s) -
Hayes Siobhan,
Ouellet Daniele,
Zhang Jianping,
Wire Mary B.,
Gibiansky Ekaterina
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010383019
Subject(s) - eltrombopag , medicine , dosing , platelet , pharmacodynamics , thrombocytopenic purpura , pharmacokinetics , gastroenterology , thrombopoiesis , population , immune system , immunology , immune thrombocytopenia , pharmacology , megakaryocyte , biology , genetics , stem cell , environmental health , haematopoiesis
The relationship between plasma eltrombopag concentrations and increases in platelet counts (PLTC) was characterized in healthy volunteers (HVs) and patients with immune thrombocytopenic purpura (ITP) using population pharmacokinetic/pharmacodynamic (PK/PD) models. The semiphysiological model included 3 PK, 1 precursor production, 2 maturation, and 1 blood platelet compartments and assumed a linear increase in platelet production rate with eltrombopag concentrations. Thrombopoiesis was assumed to be the same in HVs and patients, whereas platelets degraded more rapidly in patients. A mixture model was used, with nonresponders accounting for 19% of the patients. The following covariates were predictive of higher PLTC in ITP patients based on PK or PD differences in descending order of magnitude: East Asian race, age 65 years or older, baseline PLTC greater than 15 Gi/L, female, and concurrent corticosteroid. Simulations support starting eltrombopag at a dose of 50 mg once daily, except in East Asian patients, for whom 25 mg once daily is warranted. Doses can be titrated at 2‐week intervals (or longer) to achieve target PLTC.