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J Clin Pharmacol. 2011 Oct;51(10):1403-17. doi: 10.1177/0091270010383019. Epub 2010 Dec 8.

Population PK/PD modeling of eltrombopag in healthy volunteers and patients with immune thrombocytopenic purpura and optimization of response-guided dosing.

Author information

1
ICON Development Solutions, Ellicott City, Maryland, USA. Siobhan.hayes@iconplc.com

Abstract

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.

PMID:
21148042
DOI:
10.1177/0091270010383019
[Indexed for MEDLINE]

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