title: Population PK/PD modeling of eltrombopag in healthy volunteers and patients with immune thrombocytopenic purpura and optimization of response-guided dosing.
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.
authors.affiliation: ICON Development Solutions, Ellicott City, Maryland, USA. Siobhan.hayes@iconplc.com
authors.forename: Siobhan
authors.initials: S
authors.lastname: Hayes
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wire
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Gibiansky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D044466:Asian People; D001565:Benzoates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016022:Case-Control Studies; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy*; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; C520809:eltrombopag