Daniel Moj1, Hannah Britz1, Jürgen Burhenne2, Clinton F Stewart3, Gerlinde Egerer4, Walter E Haefeli2, Thorsten Lehr5. 1. Department of Pharmacy, Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany. 2. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. 3. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. 4. Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany. 5. Department of Pharmacy, Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany. Thorsten.Lehr@mx.uni-saarland.de.
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 Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data.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.
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.
Entities:
Keywords:
Histone deacetylase; Pediatrics; Pharmacodynamics; Physiologically based pharmacokinetics; Thrombocytopenia; Vorinostat
Authors: Eric H Rubin; Nancy G B Agrawal; Evan J Friedman; Pamela Scott; Kathryn E Mazina; Linda Sun; Lihong Du; Justin L Ricker; Stanley R Frankel; Keith M Gottesdiener; John A Wagner; Marian Iwamoto Journal: Clin Cancer Res Date: 2006-12-01 Impact factor: 12.531
Authors: William Kevin Kelly; Owen A O'Connor; Lee M Krug; Judy H Chiao; Mark Heaney; Tracy Curley; Barbara MacGregore-Cortelli; William Tong; J Paul Secrist; Lawrence Schwartz; Stacy Richardson; Elaina Chu; Semra Olgac; Paul A Marks; Howard Scher; Victoria M Richon Journal: J Clin Oncol Date: 2005-05-16 Impact factor: 44.544
Authors: Elise A Olsen; Youn H Kim; Timothy M Kuzel; Theresa R Pacheco; Francine M Foss; Sareeta Parker; Stanley R Frankel; Cong Chen; Justin L Ricker; Jean Marie Arduino; Madeleine Duvic Journal: J Clin Oncol Date: 2007-06-18 Impact factor: 44.544
Authors: Wm Kevin Kelly; Victoria M Richon; Owen O'Connor; Tracy Curley; Barbara MacGregor-Curtelli; William Tong; Mark Klang; Lawrence Schwartz; Stacie Richardson; Eddie Rosa; Marija Drobnjak; Carlos Cordon-Cordo; Judy H Chiao; Richard Rifkind; Paul A Marks; Howard Scher Journal: Clin Cancer Res Date: 2003-09-01 Impact factor: 12.531
Authors: Elizabeth Neumann; Huma Mehboob; Jacqueline Ramírez; Snezana Mirkov; Min Zhang; Wanqing Liu Journal: Front Pharmacol Date: 2016-11-16 Impact factor: 5.810
Authors: Antje-Christine Walz; Arthur J Van De Vyver; Li Yu; Marc R Birtwistle; Nevan J Krogan; Mehdi Bouhaddou Journal: Pharmacol Ther Date: 2022-02-18 Impact factor: 13.400