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Cancer Chemotherapy and Pharmacology

, Volume 80, Issue 5, pp 1013–1026 | Cite as

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification

  • Daniel Moj
  • Hannah Britz
  • Jürgen Burhenne
  • Clinton F. Stewart
  • Gerlinde Egerer
  • Walter E. Haefeli
  • Thorsten Lehr
Original Article

Abstract

Purpose

This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach.

Methods

A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration–time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi.

Results

The PBPK/PD model suggests dosages of 80 and 230 mg/m2 for children of 0–1 and 1–17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%.

Conclusions

Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.

Keywords

Vorinostat Pediatrics Physiologically based pharmacokinetics Histone deacetylase Thrombocytopenia Pharmacodynamics 

Notes

Acknowledgements

The analyses of vorinostat were supported by Merck & Co., Inc., USA that provided deuterium-labeled and unlabeled reference standards of vorinostat and its metabolites M1 and M2. Some of the studies were financially supported by MSD Sharp & Dohme GmbH, Germany.

Compliance with ethical standards

Ethical standards

All procedures performed in studies involving human participants were in accordance with the legal requirements and ethical standards of the responsible institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants before inclusion.

Conflict of interest

Daniel Moj, Hannah Britz, Thorsten Lehr and Clinton F. Stewart have reported no potential conflicts of interest. Walter E. Haefeli and Jürgen Burhenne have received financial and non-financial (analytical standards) support from Merck & Co., Inc., USA for the development and application of the vorinostat assay. Jürgen Burhenne has received travel support and lecture fees from MSD Sharp & Dohme GmbH, Germany.

Supplementary material

280_2017_3447_MOESM1_ESM.docx (5.8 mb)
Supplementary material 1 (DOCX 5969 KB)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Daniel Moj
    • 1
  • Hannah Britz
    • 1
  • Jürgen Burhenne
    • 4
  • Clinton F. Stewart
    • 2
  • Gerlinde Egerer
    • 3
  • Walter E. Haefeli
    • 4
  • Thorsten Lehr
    • 1
  1. 1.Department of Pharmacy, Clinical PharmacySaarland UniversitySaarbrueckenGermany
  2. 2.Department of Pharmaceutical SciencesSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of Hematology, Oncology, and RheumatologyHeidelberg University HospitalHeidelbergGermany
  4. 4.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of HeidelbergHeidelbergGermany

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