Semi-mechanistic thrombocytopenia model of a new histone deacetylase inhibitor (HDACi) in development, with a drug-induced apoptosis of megakaryocytes.
Q. Chalret du Rieu (1, 2), S. Fouliard (2), M. White-Koning (1), Anne Jacquet (3), Ioana Kloos (3), Stephane Depil (3), E. Chatelut (1), M. Chenel (2)
(1) Institut Claudius Regaud, Toulouse, France; (2) Clinical Pharmacokinetic department, Institut de Recherches Internationales Servier, Suresnes, France, (3) Oncology business Unit, Institut de Recherches Internationales Servier, Suresnes, France
Objectives: To develop a semi mechanistic thrombocytopenia model of a new HDAC inhibitor in development, taking into account the pharmacological knowledge of the molecule. Therefore, the aim is to assess by modelling and simulation the compound effect on both progenitor cells and megakaryocytes. A second objective is the evaluation of structural and experimental identifiability of the final enriched model.
Methods: The study included 35 patients suffering from solid tumors who received drug S over 4-week cycles. Three dosing regimens were tested. Overall 181 platelet samples from the first treatment cycle were analyzed simultaneously with NONMEM 7.2, FOCE-I. Sequential Pharmacokinetic/Pharmacodynamic (PK/PD) modelling was performed, where individual Bayesian estimates of PK parameters were fixed from a prior PK analysis for subsequent PD modelling. Identifiability of the model was analyzed using PFIM 3.2.2 software by computing expected parameter precision of estimation using mathematical derivation of the Fisher Information Matrix, for different sampling designs [1]. The structural and experimental identifiabilities of the model were evaluated by estimating each parameter's standard errors with respectively a rich design (14 platelets samples) and the sampling design used in a clinical protocol (4 platelet samples).
Results: A basic model incorporating a stem cell proliferation inhibition drug effect was developed with the same structure as Friberg et al's semi-mechanistic myelosuppression model [2-3]. Extended models were developed with an additional drug-induced megakaryocyte apoptosis. Models evaluation by individual fits analysis, goodness of fit plots and Normalized Prediction Distribution Error (NPDE) graphs, showed that both basic and extended models are able to adequately describe and predict available data [4]. All these models were shown structurally and experimentally identifiable, allowing the expectation of a good precision of estimation of model parameters for both an experimental and a richer sampling design.
Conclusions: A semi-mechanistic thrombocytopenia model, which increased pharmacological description of drug effect by mimicking the thrombocytopenic mechanism of drug S was developed. Clinical data supported a refined model, which was able to adequately describe and predict the time-course of platelets following administration of drug S.
References:
[1]. Bazzoli C, Retout S, Mentre F: Design evaluation and optimisation in multiple response nonlinear mixed effect models: PFIM 3.0. Comput Methods Programs Biomed 98:55-65, 2009
[2]. Friberg LE, Freijs A, Sandstrom M, et al: Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats. J PharmacolExpTher 295:734-40, 2000
[3]. Friberg LE, Henningsson A, Maas H, et al: Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J ClinOncol 20:4713-21, 2002
[4]. Brendel K, Comets E, Laffont C, et al: Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 23:2036-49, 2006
