Quyen Thi Tran (1), Sungwoo Goo (2), Heeyoon Jung (2), Min-Kyoung Kim (3), Jung-Hyuck Park (3), Hwi-yeol Yun (1,2)
(1) College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; (2) Department of Bio-AI convergence, Chungnam National University, Daejeon, Republic of Korea; (3) NEXEL Co., Ltd, Seoul, Republic of Korea
Objectives: NP-011 is a new human recombinant protein produced by the structural truncation of milk fat globule-EGF factor 8. NP-011 suppresses transforming growth factor β signaling rapidly and effectively associated with integrin binding for deactivating hepatic stellate cells and high productivity, and therefore enhance its therapeutic efficacy against liver fibrosis [1]. The present work aimed to characterize the pharmacokinetics (PK) of NP-011 in animals with integrated analysis of intravenous (IV) and subcutaneous (SC), single- and multiple-dose administrations. Then the developed population PK model was used to optimize dose for further studies.
Methods: The pre-clinical studies evaluated the pharmacokinetics of NP-011 in animals following single intravenous administrations (three escalation dose in each animal, mouse and monkey) or multiple subcutaneous administrations (two doses in each animal, mouse and monkey). Measurable serum concentrations in intravenous and subcutaneous were merged into one to develop population PK models using non-linear mixed-effect modeling (NONMEM version 7.5.0). For model evaluation, a bootstrap resampling using 1000 replicates and visual predictive checks stratified for dose and route using 1000 simulated datasets of individuals from the original dataset were used. To optimize dose for further studies, area under the time-concentration curve (AUC) was used as target. Where, predicted AUC derived from IV dose in pharmacodynamic experiment was set as target to find the SC dose which would have the similar AUC in IV route.
Results: A two-compartment model with a first-order absorption, first-order elimination and route-based clearance adequately described NP-011 pharmacokinetics in animals. In mouse, due to high inter-individual variability at SC low dose, the final population PK model was structured using IV and SC high dose. NP-011 clearance, inter-compartmental clearance, central and peripheral volume of distribution were 0.363 L/h/kg for IV (0.102 L/h/kg for SC), 0.007 L/h/kg, 0.076 L/kg, and 0.062 L/kg in mouse, and 0.090 /h/kg for IV (0.012 L/h/kg for SC), 0.004 L/h/kg, 0.046 L/kg, and 0.020 L/kg in monkey, respectively. Bioavailability for subcutaneous administration was approximately 4 % and 2.04 % in mouse and monkey, respectively. For dose optimization, in mouse, NP-011 0.56 mg/kg and 6.0 mg/kg twice-weekly (BIW) in SC route were expected to achieve the same AUC as 0.08 mg/kg and 0.85 mg/kg BIW in IV route, respectively. In monkey, to have the similar AUC of 0.04 mg/kg and 0.68 mg/kg BIW in IV route, NP-011 should be given at 0.28 mg/kg and 4.4 mg/kg BIW in SC route.
Conclusions: Pharmacokinetics of NP-011, a truncated form of MFG-E8, were well described with two-compartment model. This promising new therapeutic strategy for treating fibrosis diseases will be evaluated after releasing pharmacodynamic data and confirmed by pharmacokinetics/pharmacodynamics model. This work is expected to perform in the near future.
References:
[1] An, G.H.; Lee, J.; Jin, X.; Chung, J.; Kim, J.C.; Park, J.H.; Kim, M.; Han, C.; Kim, J.H.; Woo, D.H. Truncated milk fat globule-EGF-like factor 8 ameliorates liver fibrosis via inhibition of integrin-TGfβ receptor interaction. Biomedicines 2021, 9, 1–15.
Reference: PAGE 30 (2022) Abstr 9981 [www.page-meeting.org/?abstract=9981]
Poster: Drug/Disease Modelling - Other Topics