(M-085) PBPK-mQSP Model Analysis of KHK4951, an Eye Drop Formulation of Tivozanib, a Potent and Selective VEGF Receptor Inhibitor

Stephan Schaller, Dr. – CEO, ESQlabs GmbH; Pavel Balazki, MSc – Senior Scientist, ESQlabs GmbH; Marco Albrecht, PhD – Scientist, Systems Pharmacology, ESQlabs GmbH; Walter Schmitt, Dr. – Scientific Advisor, ESQlabs GmbH; Tomonori Tayama, MSc – Associate Director, Clinical Pharmacology, Medical Pharmacology, Kyowa Kirin Co., Ltd.,; Matthew Hruska, PharmD, PhD, FCP – Vice President, Global Head of Clinical Pharmacology, Clinical Pharmacology, Kyowa Kirin, Inc.; Douglas Marsteller, PhD – Senior Director, Pharmacometrics, Clinical Pharmacology, Kyowa Kirin, Inc.

Objectives: KHK4951 is a sterile ophthalmic suspension of tivozanib hydrochloride monohydrate, a potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor, being developed for the treatment of retinal vascular diseases. The objective of this analysis was to develop a physiologically-based pharmacokinetic (PBPK) and minimal quantitative systems pharmacology (mQSP) models to support the ongoing development of KHK4951.

Methods: A whole-body PBPK model of tivozanib for animals and human was developed using serum drug concentration data after oral and ocular administration. The Open Systems Pharmacology Suite version 11.1 [1] was used for the modeling. The generic PBPK model structure was extended to include ocular compartments and parameterized using collected physiological parameters and ocular tissue drug concentration data from animals. Published physiological parameters were used for extrapolation to human. The structure of the ocular model was constructed based on published models [2, 3]. The PBPK model was extended with the mQSP model, including a disease progression and effect models. The mQSP model was developed based on published models for anti-VEGF biologics [4, 5]. This model was extended with mechanistic structures relating VEGF to VEGFR binding, VEGF inhibition by intravitreal injection of the anti-VEGF biologics, and VEGFR inhibition by tivozanib. Changes in central subfield thickness (CST) and best corrected visual acuity (BCVA) were mathematically linked to the changes in VEGF-VEGFR complex levels. Published clinical study data were used for model calibration. VEGFR-mediated drug effects of KHK4951 were calibrated using data from a clinical study (NCT04594681).

Results: Serum and tissue concentrations in animals and human were well characterized using the PBPK model. The predicted mean tivozanib serum and tissue concentrations generally reproduced the observed concentrations after oral and ocular administrations in animals and human. The mQSP model was able to predict previously published aflibercept studies; the predicted percentages of patients experiencing a decrease in BCVA of 15 letters or more over 52 weeks were 7.3% after aflibercept treatment and 36% after sham injections, consistent with the HAWK study (5.6%) [6] and the MARINA study (38%) [7].

Conclusions: The PBPK-mQSP model was developed to characterize the PK of tivozanib both systemically and in the eye and to predict BCVA responses after ocular administration. The model adequately characterized serum (in animals and human) and tissue (in animals) concentrations after ocular administration. The model also accurately characterized disease progression and anti-VEGF treatment efficacy. Therefore, the model could potentially be helpful in clinical development efforts involving tivozanib.

Citations: [1] www.open-systems-pharmacology.org
[2] Le Merdy et al, Pharm Res.37:245 (2020)
[3] Anna-Kaisa Rimpelä (2018), https://helda.helsinki.fi/handle/10138/235367
[4] Mulyukov et al, CPT Pharmacometrics Syst Pharmacol. 7:660 (2018)
[5] Luu et al, J Clin Pharmacol. 62:594 (2022)
[6] Dugel et al, Ophthalmology. 128:89 (2021)
[7] Rosenfeld et al, N Engl J Med. 35:1419 (2006)