Xu Jiang, Jun Seok Cha, Minkyu Choi, Byung Hak Jin, Choon Ok Kim, Dongwoo Chae
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
Objectives:
Filgrastim is a well-known granulocyte colony-stimulating factor (G-CSF), a cytokine for the maturation and mobilization of bone marrow neutrophils. It is present at low levels in healthy individuals and at increased levels in infections and inflammations. It can stimulate the activation, proliferation, differentiation, maturation, and survival of neutrophil precursor cells in the bone marrow as well as enhancing mature neutrophil cell function. Peripheral blood CD34+ cells mobilized by G-CSF administration are potentially useful for transplantation and as a target of gene transfer for the therapy of hematopoietic disorders. This study aimed to develop a population pharmacokinetic (PK) – pharmacodynamic (PD) model of filgrastim with regards to peripheral blood CD34+ cell counts.
Methods:
The plasma filgrastim concentration and CD34+ cell counts data were obtained from a randomized, open-label, two-way crossover bioequivalence study in healthy Korean subjects after a single-dose subcutaneous administration of Neupogen® (Amgen Inc., Thousand Oaks, CA, USA) and its biosimilar Leucostim® (Dong-A Pharmaceutical Co. Ltd., Republic of Korea) (NCT02725086). [1] The blood sampling time points of filgrastim and CD34+ cell counts were at pre-dose (0h), 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h and pre-dose (0h), 24h, 48h, 72h, 96h, 120h, 168h, 240h, 312h after administration, respectively. A population PK-PD model was constructed by using a nonlinear mixed effects approach (Monolix® Suite 2021R1). Seventeen potential covariates, interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots and visual predictive checks (VPCs).
Results:
A total of 1378 plasma concentrations and 982 CD34+ cell counts data were collected from 53 subjects (26 subjects from 5 mcg/kg dose group and 27 subjects from 10 mcg/kg dose group) and were used in the PK-PD model development and evaluation. The PK of filgrastim was adequately described with a one-compartment linear disposition model combined with transit compartments for absorption. The log-transformed body weight was the only meaningful covariate that significantly influenced the volume of distribution. The population parameter estimates for the volume of distribution (V) clearance (CL), absorption rate constant (ka), mean transit time (Mtt), and the number of transit compartment were 5.57L, 1.55L/h, 0.44/h, 5.47h, 0.87, respectively. CD34+ cell mobilization was best described by a model assuming continual entry of proliferating bone marrow stem cells into the peripheral blood via a single transit compartment. The transit and elimination rate constants were assumed identical to ensure parameter identifiability, and were estimated as 0.057/h. The GOF plots and VPCs of the final model suggested that the proposed model was adequate and robust with good precision at different dose strengths.
Conclusions:
We successfully developed a PKPD model of G-CSF to optimize the yield of CD34+ cells for use in stem cell transplantation. Our study is expected to enable efficient determination of the optimal G-CSF dose and the harvesting of peripheral blood CD34+ cells.
References:
[1] Choi, C., et al., Comparison of biosimilar filgrastim with a reference product: pharmacokinetics, pharmacodynamics, and safety profiles in healthy volunteers. Drug Des Devel Ther, 2018. 12: p. 2381-2387.
Reference: PAGE 32 (2024) Abstr 10841 [www.page-meeting.org/?abstract=10841]
Poster: Clinical Applications