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Population Pharmacokinetic and Pharmacodynamic Modeling of Lusutrombopag, a Newly Developed Oral Thrombopoietin Receptor Agonist, in Healthy Subjects

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Abstract

Objectives

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.

Methods

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.

Results

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 E max model 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.

Conclusion

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.

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Authors and Affiliations

  1. Clinical Research Department, Shionogi & Co., Ltd., 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan

    Takayuki Katsube, Toru Ishibashi & Toshihiro Wajima

  2. Global Project Management Department, Shionogi & Co., Ltd., Kita-ku, Osaka, Japan

    Takeshi Kano

Authors
  1. Takayuki Katsube
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  2. Toru Ishibashi
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  3. Takeshi Kano
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  4. Toshihiro Wajima
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Corresponding author

Correspondence to Takayuki Katsube.

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Conflict of interest

The authors, Takayuki Katsube, Toru Ishibashi, Takeshi Kano, and Toshihiro Wajima, are all employees of Shionogi & Co., Ltd.

Funding

This study was supported by Shionogi & Co., Ltd.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 27 kb)

40262_2016_411_MOESM2_ESM.tiff

Supplementary material 2 (TIFF 12656 kb) Supplemental Fig. S1 Relationships of empirical Bayes-estimated CL/F or V2/F of the base model and background data. Open circles: parameters of Japanese subjects. Closed circles: parameters for non-Japanese subjects. Solid line: a LOESS smoother line. Box plot: a thick center line represents the median, top, and base of the box represent the first and third quartiles [interquartile range (IQR)], whiskers represent the most extreme data within 1.5 × IQR, and circles represent outliers beyond 1.5 × IQR. CL/F apparent total clearance, V2/F apparent central volume, Jpn Japanese, Non Jpn non-Japanese

40262_2016_411_MOESM3_ESM.tiff

Supplementary material 3 (TIFF 21357 kb) Supplemental Fig. S2 Goodness-of-fit plots for the final PK model. Solid line: y = x in upper figures and y = 0 in lower figures. Dotted line: a LOESS smoother line. DV observed data, CWRES conditional weighted residuals, IPRED individual-predicted data, PK/PD pharmacokinetic/pharmacodynamic, PRED population-predicted data

40262_2016_411_MOESM4_ESM.tiff

Supplementary material 4 (TIFF 6328 kb) Supplemental Fig. S3 Relationships of empirical Bayes-estimated EC50 of the base model and background data. Open circles: parameters of Japanese subjects. Closed circles: parameters for non-Japanese subjects. Solid line: a LOESS smoother line. Box plot: a thick center line represents the median, top, and base of the box represent the first and third quartiles [interquartile range (IQR)], whiskers represent the most extreme data within 1.5 × IQR, and circles represent outliers beyond 1.5 × IQR. EC 50 plasma S-888711 concentration achieving 50 % of Emax, Jpn Japanese, Non Jpn non-Japanese

40262_2016_411_MOESM5_ESM.tiff

Supplementary material 5 (TIFF 21357 kb) Supplemental Fig. S4 Goodness-of-fit plots for the final PK/PD model. Solid line: y = x in upper figures and y = 0 in lower figures. Dotted line: a LOESS smoother line. DV observed data, CWRES conditional weighted residuals, IPRED individual-predicted data, PK/PD pharmacokinetic/pharmacodynamic, PRED population-predicted data

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Katsube, T., Ishibashi, T., Kano, T. et al. Population Pharmacokinetic and Pharmacodynamic Modeling of Lusutrombopag, a Newly Developed Oral Thrombopoietin Receptor Agonist, in Healthy Subjects. Clin Pharmacokinet 55, 1423–1433 (2016). https://doi.org/10.1007/s40262-016-0411-6

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  • DOI: https://doi.org/10.1007/s40262-016-0411-6

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