A physiologically-based pharmacokinetic model for V937, a novel oncolytic virus, in mice
Sara Peribañez-Dominguez (1,2), Zinnia P Parra-Guillén(1,2),Tomoko Freshwater(3), Iñaki F Troconiz (1,2,4)
(1) Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain, (2) Navarra Institute for Health Research (IdiSNA), Pamplona, Spain, (3) Quantitative Pharmacology and Pharmacometrics Immune/Oncology (QP2-I/O) Merck & Co., Inc., Rahway, New Jersey, USA. (4) Institute of Data Science and Artificial Intelligence, DATAI, University of Navarra, Pamplona, Spain.
Introduction/Objectives: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune induced tumor lysis [1,2]. Despite the number of ongoing OVs development programs already in their clinical phases, the mechanisms governing pharmacokinetics (PK) and the induced antitumor response are still poorly understood. This work aims to develop a physiologically-based pharmacokinetic (PBPK) model of the novel oncolytic virus V937 in non-tumor bearing mice to get a quantitative understanding of its elimination and tissue uptake processes.
Methods: Model development was performed using data obtained from 60 Hu/Mu chimeric ICAM-1 transgenic Balb-C mice (30 female and 30 male). Briefly, a single intravenous V937 dose of 2.5 x 107 TCID50 (50% tissue culture infectious dose) was administered through the tail vein. At study days 1, 3, 7, 10, and 14, mice were sacrificed (n= 12 in each time point) and V937 viral levels (copies/µg RNA) were quantified by quantitative polymerase chain reaction from 8 different tissues/organs (lung, brain, heart, muscle, pancreas, spleen, liver, kidney and lymph node). An external dataset was used for model validation. This test set included multiple dose experiments with different routes of administration.
V937 distribution in each of the organ in which viral copies were available was described using a physiologically structure based on mouse specific organ blood flows (Q) and volumes (V) [3]. Homogenous (perfusion-limited) and non-homogenous distribution of V937 within each compartment, as well as non-linear tissue uptake consequence of an eventual saturation of the ICAM-1 membrane receptors were considered during model building. Analyses were performed using the non-linear mixed effects approach with NONMEM 7.4.
Results: A PBPK model characterizing concentration vs time profiles of V937 in different organs of non-tumor bearing mice receiving a single intravenous dose was successfully developed. After IV dose, viral levels showed a marked drop from 108 to 105 copies/µg RNA at day 1, reflected in a high estimate of total clearance (18.2 mL/h) similar to values published in literature [2]. The organs with the highest virus concentrations were lung, muscle and heart reaching values between 105 and 106 copies/µg RNA. The estimates of the partition coefficient ranged from 9.94 10-3 to 548. A well-stirred (homogeneous distribution) model provided an adequate description for all organs except muscle and heart, where a saturable uptake process improved data description with estimates of the Michaelis-Menten constant of 0.568 and 0.038 copies/ml, respectively. Simulations revealed that the model described well the organ exposure to V937 after different dosing designs and routes of administration.
Conclusions: To the best of our knowledge, this is the first PBPK model developed to characterize OV biodistribution, thus representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OV could replicate, in order to explore its impact on viral kinetics and tumor response further supporting OV development programs.
References:
[1] Haseley A, Alvarez-Breckenridge C, Chaudhury AR, Kaur B. Advances in oncolytic virus therapy for glioma. Recent Pat CNS Drug Discov. 2009;4(1):1–13.
[2] Parra-Guillen ZP, Freshwater T, Cao Y, Mayawala K, Zalba S, Garrido MJ, et al. Mechanistic Modeling of a Novel Oncolytic Virus, V937, to Describe Viral Kinetic and Dynamic Processes Following Intratumoral and Intravenous Administration. Front Pharmacol. 2021;12(July):1–13.
[3] PK-Sim Documentation - Open Systems Pharmacology. Docs.open-systems pharmacology.org. Available from: https://docs.open-systems pharmacology.org/working-with-pk-sim/pk-sim-documentation/