A new population PK/PD model to assess the myelotoxicity of candidate drugs in preclinical and in clinical studies
F. Del Bene (2), N. Terranova (1), F. Fiorentini (2), M. Germani (2), P. Magni (1)
(1) Dipartimento di Informatica e Sistemistica, Università degli Studi di Pavia, Pavia, Italy; (2) ACCELERA srl , Nerviano, Italy
Objectives: Bone marrow suppression or myelotoxicity is a serious side effect of chemotherapy and drugs affecting the immune system inducing neutropenia and leucopenia, conditions that can lead to infections and fever. The risk is especially high in cytotoxic chemotherapy for leukemia. A new population PK/PD approach can be adopted during the different phases of drug development to test and select new candidate compounds devoid of myelosuppression effects preserving the therapeutic efficacy.
Methods: Myelotoxic adverse effect was evaluated using a recently developed semi-mechanistic PK/PD model, characterized by a dynamical system with non-linear feedback [1]. The aim was to describe leukocytes or neuthrophils peripheral concentrations during and after the treatment in order to predict the minimum concentration (nadir), and the time necessary to reach that concentration (time-to-nadir).
Results: The proposed model was implemented in NONMEM and successfully applied to analyzed different datasets. Preliminary results indicate that it is able to describe experimental data also in a population context and that it can be used to rank compounds on the basis of their myelotoxicity.
Conclusions: PK/PD modeling approaches can impact each different phase of R&D process to characterize drug myelotoxicity for improving drug development plan, enabling critical decision making, and eventually bringing safe and effective medicines to patients. Overall, the results of myelotoxicity testing were consistent allowing to predict human neutropenia grade from animal PK/PD data. The human PK/PD model can be also used for saving resources and time during dose escalation.
References:
[1] N. Politi, A. Russu, F. Fiorentini, M. Germani, M. Rocchetti, G. De Nicolao, P. Magni (2010). Modeling myelosuppression in patients treated with anticancer drugs, Patron, p. 135-136, ISBN/ISSN:9788855530828
