Application of a physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat to improve dosing regimens in adults
Daniel Moj (1), Hannah Britz (1), Gerlinde Egerer (2), Walter Emil Haefeli (3) and Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany, (2) Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany, (3) Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
Objectives: First, to develop a PBPK model of the HDAC inhibitor vorinostat for adults [1]. Second, to link the PBPK model with (i) an HDAC-activity PD model (efficacy marker) and (ii) a thrombocytopenia PD model (safety marker). Third, to use the developed PBPK/PD model to identify vorinostat dosing regimens possibly superior to the standard treatment.
Methods: PK, PD, physicochemical, and ADME data were obtained from published literature and unpublished in-house data. For the PBPK model, 11 clinical studies (355 patients) administering single intravenous (75–900 mg/m2) or single/multiple oral doses (100-800 mg) of vorinostat were split into a development and an evaluation dataset. When necessary, parameters were estimated based on the development dataset. For the PD models, 2 clinical studies after single and multiple doses of 400 mg daily were available including 73 patients. Both PD models were linked to intracellular bone concentrations of vorinostat. An indirect response model was used to model the HDAC-activity with vorinostat increasing kout. Thrombocytopenia during a 36 weeks treatment was modelled using an expanded Friberg model [2]. Model parameters were based on literature results of 8 studies, mean parameter values were used for simulation and the vorinostat slope parameter was estimated. The full PBPK/PD model was used to simulate various dosing regimens. Modeling and simulation was performed using PK-Sim® 6.3.2, MoBi® 6.3.2, and Matlab® 2013b.
Results: A vorinostat PBPK/PD model was successfully developed. Development and evaluation datasets were excellently described and predicted. The ratios of predicted vs. reported AUC0->inf (n=52), Cmax (n=54), Tmax (n=41), and half-life (n=49) were 1.00, 1.00, 0.99, and 1.06, respectively. The standard vorinostat dosing scheme of 400 mg daily led to a steady-state thrombocyte count of 193*109 cells/L and a maximum HDAC-activity reduction to 37%. The most favourable dosing regimen (2 h intravenous infusion, 7 daily doses, every second week) resulted in a maximum HDAC-activity reduction (Emax) to 23%, without altering the thrombocyte count. In general, single oral daily doses were superior to two and three daily doses.
Conclusions: The successfully developed PBPK/PD model of vorinostat identified new dosing regimens for vorinostat chemotherapy, which could significantly increase HDAC inhibition and thus possibly treatment effectiveness without increasing the risk of thrombocytopenia.
References:
[1] Iwamoto M, Friedman EJ, Sandhu P, Agrawal NG, Rubin EH, Wagner JA. Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. Cancer Chemother Pharmacol (2013) 72(3): 493-508.
[2] Chalret du Rieu Q, Fouliard S, White-Koning M, Kloos I, Chatelut E, Chenel M. Pharmacokinetic/Pharmacodynamic modeling of abexinostat-induced thrombocytopenia across different patient populations: application for the determination of the maximum tolerated doses in both lymphoma and solid tumour patients. Invest New Drugs (2014) 32(5): 985-94.