Arai Hayato (1), Masaki Saito (1), Masaharu Komeno (1), Susumu Nakade(1)
(1) Ono Pharmaceutical Co., Ltd., Osaka, Japan
Objectives: ONO-7269 can be administered intravenously and is expected to exert an antithrombotic effect by inhibiting activated blood coagulation factor XI (FXIa). FXIa inhibitors are expected to be anticoagulants with no bleeding promoting effect[1]. Activated partial thromboplastin time (APTT) is a blood test that characterizes blood clotting, and the APTT ratio is also used to monitor the therapeutic effect of heparin, a widely prescribed drug that reduces blood clotting tendency. A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ONO-7269 after continuously intravenous administration in healthy adult Japanese men and Japanese renal impairment subjects. During the Phase 1, APTT was assessed to evaluate the pharmacodynamics of ONO-7269. A PK/PD modeling analysis was conducted to clarify the relationship between plasma ONO-7269 concentration and APTT to support the determination of ONO-7269 dosing regimens.
Methods: This Phase 1 study had three parts consisting of a 24-hour continuously intravenous administration part, a 5-day continuously intravenous administration part, and a renal dysfunction part. ONO-7269 was intravenous infusion administered at doses of 9.6 and 432 mg to evaluate the time-course of plasma ONO-7269 concentration and APTT. ONO-7269 PK data and APTT ratio data were pooled from the phase 1 study including 44 healthy subjects and 12 renal dysfunction subjects. Pop PK model and concentration-APTT ratio relationship model were developed in a sequential manner. The resulting data were integrated and empirical model analyses were performed with NONMEM. The final pop PK model was linked to the concentration-APTT ratio relationship model to simulate various doses of ONO-7269.
Results: Plasma concentration of ONO-7269 was best described with a 3-compartment model. Following a step-wise covariate analysis, effect of estimated glemerular filtration rate (eGFR) and body weight were included in the Pop PK model. The predictive abilities of the PK models were confirmed with VPC plots. Concentration-APTT ratio relationship model was well described by Emax and linear model, and double Emax model. Following a step-wise covariate analysis, effect of baseline of APTT was included in the exposure–response model. These predictive abilities of the exposure–response models were confirmed with VPC plots. In both models, the relationship between concentration and APTT was the same in subjects with renal impairment as in healthy subjects. As the defference between two modeles, the double Emax model suggested that APTT tended to be plateau near high dose although the Emax and linear model did not. It was difficult to distinguish between the two models without the high dose of data. Considering safety around high doses, we adopted the Emax and linear model. Finally, trial simulations were performed when ONO-7269 was administered to a virtual patient, indicating a derived dose response.
Conclusions: Simulation results using the linked PK/PD model showed a dose at which ONO-7269 could be safely administered.
References:
[1] Schumacher WA, Luettgen JM, Quan ML, Seiffert DA. Inhibition of factor XIa as a new approach to anticoagulation. Arterioscler Thromb Vasc Biol. 2010;30:388-92.
Reference: PAGE () Abstr 9273 [www.page-meeting.org/?abstract=9273]
Poster: Drug/Disease Modelling - Other Topics