Chihiro Hasegawa (1,2), Helen Kastrissios (3), Jonathan Monteleone (3), Tomoya Ohno (1), Takeo Umemura (1), Michiyo Ohyama (4), Shinichi Nagase (5), Maria Small (5), Steve Deacon (5), Mikio Ogawa (1), Ichiro Ieiri (2)
(1) Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd, (2) Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, (3) Strategic Consulting Services, Pharsight Corporation, (4) Clinical Development Planning, Ono Pharmaceutical Co., Ltd, (5) Drug Development, ONO PHARMA UK LTD
Objectives: ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The pharmacokinetic (PK) and pharmacodynamic (PD) properties of ONO-5334 were assessed in order to support dose and formulation (immediate release tablet, sustained release tablet) selection for future trials.
Methods: The population PK-PD (exposure-response) modeling was performed using NONMEM based on plasma concentrations of ONO-5334 and PD markers. As PD markers, serum bone resorption markers and bone mineral density (BMD) responses were obtained in phase 1 and 2 trials, respectively, and used for modeling. With the use of the developed models, PD markers after administration of ONO-5334 SRT (sustained release tablet) as well as IRT (immediate release tablet) were simulated. BMD responses were simulated where only BMD response after administration of IRT had been studied to date, using PK model developed with SRT phase 1 data and exposure-response model developed with IRT phase 2 data.
Results: With the indirect response model ONO-5334 was assumed to inhibit the zero order production rate of serum bone resorption markers [1,2]. Relationships between ONO-5334 exposure and BMD responses were modeled using direct response models [3]. As an exposure metric, trough concentrations of ONO-5334 were selected which support the necessity of sustained plasma concentration over 24 hours. The simulation results showed that ONO-5334 SRT should provide comparable PD markers at a lower dose relative to IRT.
Conclusions: The modeling & simulation with PD markers led to the acquisition of useful information for selecting appropriate dose and formulation in the future trial.
References:
[1] Pillai G, Gieschke R, Goggin T, Jacqmin P, Schimmer RC, Steimer JL. A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br J Clin Pharmacol. 2004;58:618-631.
[2] Zierhut ML, Gastonguay MR, Martin SW, et al. Population PK-PD model for Fc-osteoprotegerin in healthy postmenopausal women. J Pharmacokinet Pharmacodyn. 2008;35:379-399.
[3] Stone J, Zajic S, Dykstra K, et al. Population PK/PD modeling of lumbar spine bone mineral density response to 12 months of treatment with the cathepsin K inhibitor, odanacatib, and simulations to further evaluate the dose-response relationship [ACoP 2008, Arizona]. http://tucson2008.go-acop.org/pdfs/63_Stone.pdf. Accessed November 5, 2013.
Reference: PAGE 23 (2014) Abstr 3054 [www.page-meeting.org/?abstract=3054]
Poster: Drug/Disease modeling - Other topics