Christina Pentafragka (1), Gilles Freyer (2) and Athanassios Iliadis (1)
(1) Aix-Marseille University, Faculty of Pharmacy, France; (2) Institut de Cancérologie des HCL, Lyon, France
Objectives: To develop a PK/PD population model to describe and compare the experimental observed profiles of two different formulations of lenograstim, a colony-stimulating factor of the hematopoietic chain, given as single and repeated doses in healthy volunteers.
Methods: PK (lenograstim concentrations) and PD (absolute neutrophil counts) data were supplied by two open-label, randomised, two-way crossover studies in which lenograstim AA (test product) and HSA (reference therapy) were administered by subcutaneous route within two periods to 16 healthy male volunteers at a single dose of 150 μg/m2 in the first, and to 24 healthy male volunteers at a dose of 10 μg/kg/day for 5 days in the second study. The basic model [1] was developed using MATLAB. For the population analysis of the experimental data, Naïve-Averaging-of-Data approach and Two-Stage method were performed by MATLAB. Single-Stage method was performed by Monolix [2].
Results: The most adequate model to describe the observed PK and PD profiles is (a) a two-compartment model for the PKs, including for the PDs (b) four differential equations depicting the maturation of neutrophils, (c) additional equations and parameters representing the down-regulation on stem cells’ stimulation and up-regulation on lenograstim’s clearance by the mature neutrophils’ levels, and (d) two acceleration and one enhancement Emax-mechanisms, illustrating the effect of lenograstim on the hematopoietic chain. Some simplifications had to be done and parameters had to be fixed in order for the model to be structurally and numerically identifiable. Given the inter-subject variability, the obtained model establishes the equivalence between the two studied formulations of lenograstim.
Conclusions: The biggest technical difficulty for this type of modeling is the closed-loop biological system, controlled by two homeostatic feedbacks. This model could be used to describe the PK/PD behavior when anticancer drugs with hematological toxicity are co-administered with lenograstim to patients [3].
References:
[1] Ostby I, Kvalheim G, Rusten LS, Gottum P. Mathematical modeling of granulocyte reconstitution after high-dose chemotherapy with stem cell support: Effect of post-transplant G-CSF treatment. J. Theor. Biol. 231:69-83(2004).[2] MONOLIX. Version 3.2, INRIA (2010).
[3] Morstyn G, Souza L, Keech J, Sheridan W, Campbell L, Alton N, Green M, Metcalf D, Fox R. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet: 667-672 (1988).
Reference: PAGE 24 (2015) Abstr 3331 [www.page-meeting.org/?abstract=3331]
Poster: Methodology - New Modelling Approaches