Chihiro Hasegawa (1), Susumu Nakade (2), Tomoya Ohno (1), Junji Komaba (2), and Mikio Ogawa (1)
(1) Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd, Japan, (2) Drug Development, Ono Pharma USA, Inc., U.S.A.
Objectives: ONO-4641 is an orally administered sphingosine 1-phosphate (S1P) receptor modulator that is currently under clinical evaluation for multiple sclerosis (MS). The pharmacokinetic (PK) and pharmacodynamic (PD) properties of ONO-4641 in MS patients were assessed in order to support dose selection for the future trial in terms of efficacy and safety.
Methods: The population PK-PD modeling was performed using NONMEM based on plasma concentrations of ONO-4641 and absolute lymphocyte counts (ALC) obtained in phase 1 trials. With the use of the developed model, a clinical trial simulation was conducted based on the study design planned for phase 2 trial.
Results: The population PK-PD model was developed using data from 83 subjects. The relationship between ALCs and plasma concentrations of ONO-4641 was described by an indirect-response model [1-3]. The indirect-response model had an Imax value of 0.991 and an IC50 value of 2.12 ng/ml for MS patients. Based on the ALC-endpoint relationship in phase 2 trial of another MS drug, the ALC suppression of >60% from baseline was believed to show the efficacy on the endpoint (number of lesions obtained with magnetic resonance imaging) [4]. The simulation results using the developed model indicated that ONO-4641 dose more than 0.1 mg produced the decrease. The suppression with lower doses was mild to moderate (30-45%), but the efficacy on the number of lesions was unknown. Further, the simulation results indicated the mean drop-out rate due to the lymphopenia of at most 3% of total patients in phase 2 trial.
Conclusions: The clinical trial simulation of ALC based on the developed population PK-PD model led to the acquisition of useful information for selecting doses in the future trial.
References:
[1] Ohno T, Hasegawa C, Nakade S, et al. The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic-pharmacodynamic modeling. Biopharm Drug Dispos (2010) 31: 396-406.
[2] Meno-Tetang GM, Lowe PJ. On the prediction of the human response: a recycled mechanistic pharmacokinetic/pharmacodynamic approach. Basic Clin Pharmacol Toxicol (2005) 96: 182-92.
[3] Rohatagi S, Zahir H, Moberly JB, et al. Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator. J Clin Pharmacol (2009) 49: 50-62.
[4] Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med (2006) 355: 1124-40.
Reference: PAGE 22 (2013) Abstr 2820 [www.page-meeting.org/?abstract=2820]
Poster: CNS