title: Population Pharmacokinetic and Pharmacodynamic Modeling of Lusutrombopag, a Newly Developed Oral Thrombopoietin Receptor Agonist, in Healthy Subjects.
abstract: The aim of this study was to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model for describing plasma lusutrombopag concentrations and platelet response following oral lusutrombopag dosing and for evaluating covariates in the PK/PD profiles.
  
  
  
  A population PK/PD model was developed using a total of 2539 plasma lusutrombopag concentration data and 1408 platelet count data from 78 healthy adult subjects following oral single and multiple (14-day once-daily) dosing. Covariates in PK and PK/PD models were explored for subject age, body weight, sex, and ethnicity.
  
  
  
  A three-compartment model with first-order rate and lag time for absorption was selected as a PK model. A three-transit and one-platelet compartment model with a sigmoid Emaxmodel for drug effect and feedback of platelet production was selected as the PD model. The PK and PK/PD models well described the plasma lusutrombopag concentrations and the platelet response, respectively. Body weight was a significant covariate in PK. The bioavailability of non-Japanese subjects (White and Black/African American subjects) was 13 % lower than that of Japanese subjects, while the simulated platelet response profiles using the PK/PD model were similar between Japanese and non-Japanese subjects. There were no significant covariates of the tested background data including age, sex, and ethnicity (Japanese or non-Japanese) for the PD sensitivity.
  
  
  
  A population PK/PD model was developed for lusutrombopag and shown to provide good prediction for the PK/PD profiles. The model could be used as a basic PK/PD model in the drug development of lusutrombopag.
authors.affiliation: Clinical Research Department, Shionogi & Co., Ltd., 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan. takayuki.katsube@shionogi.co.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Katsube
authors.affiliation: Clinical Research Department, Shionogi & Co., Ltd., 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Global Project Management Department, Shionogi & Co., Ltd., Kita-ku, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kano
authors.affiliation: Clinical Research Department, Shionogi & Co., Ltd., 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wajima
mesh_terms: D000328:Adult; D000367:Age Factors; D019540:Area Under Curve; D001835:Body Weight; D002934:Cinnamates / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D044469:Racial Groups; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D012737:Sex Factors; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D044465:White People
chemical_list: D002934:Cinnamates; D053628:Receptors, Thrombopoietin; D013844:Thiazoles; C000611387:lusutrombopag