2017 - Budapest - Hungary

PAGE 2017: Drug/Disease modelling - CNS
Jonás Samuel Pérez-Blanco

Population PK and exposure-response analysis of sleep parameters for JNJ-42847922, a novel Orexin 2 receptor antagonist

Alberto Russu (1), Jonas Samuel Pérez-Blanco (1), Peter Van Der Ark (1), Vikash Sinha (2), Adam Savitz (2), Peter De Boer (1), Jay B. Saoud (3), Partha Nandy (2), Juan Jose Perez Ruixo (1)

(1) Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium. (2) Janssen Research & Development, Titusville, NJ, USA. (3) on behalf of Minerva Neurosciences, Inc.

Objectives:  The orexin system regulates wake-sleep states. [1] Orexin 2 receptor (OX2R) blockade may be a novel pharmacological approach to treat insomnia. JNJ-42847922 is a novel, high affinity OX2R antagonist under investigation for insomnia treatment. [2, 3] The objectives of this work are: (i) to characterize JNJ-42847922 pharmacokinetics (PK) in healthy volunteers and insomnia patients, (ii) to model exposure-response (E-R) of sleep parameters (latency to persistent sleep, LPS; wake after sleep onset, WASO) in insomnia patients, with/without major depressive disorder (MDD), and (iii) to assess the impact of differences in PK (e.g. due to weight or age) on sleep parameters.

Methods:  Population PK modeling was conducted on two phase 1 studies and one phase 2 insomnia study in Caucasian and Japanese subjects dosed once-daily 3-5 hours after dinner with tablet formulation of 10, 20 or 40 mg. Physiologically plausible PK covariates were tested via stepwise covariate modeling. E-R modeling was conducted on LPS and WASO data collected via 8-hour polysomnography from three patient studies (one in insomnia patients, two in MDD patients with insomnia) using similar dosing conditions and dose range. Model building and simulations were performed in NONMEM v7.2. [4]

Results:  The PK of JNJ-42847922 was dose-proportional, with rapid absorption (Tmax ~ 1-2h) and linear elimination characterized by a 2-3h terminal half-life. Healthy volunteer and patient PK were similar. In the studies included in this analysis, a 5% decrease in clearance per 10-year age increment (from a median of 40 years) and a 30% increase in volume of distribution when doubling body weight were found. Japanese PK was similar to Caucasian PK except for 50% smaller absorption rate constant in Japanese, which resulted in slightly delayed and lower Cmax. E-R on LPS was detected in insomnia patients and in one MDD study. A 20 mg dose is expected to result in 60% LPS reduction from placebo. WASO analysis showed evidence of an E-R signal (driven by average plasma concentration) in the insomnia study (about 14 min reduction from placebo at 40 mg).

Conclusions:  The short half-life of JNJ-42847922 results in relatively low plasma concentrations at 8h post-dose, with negligible accumulation after multiple daily dosing. In insomnia patients, JNJ-42847922 administration potently reduced LPS. E-R simulations show that differences in PK identified by the covariate analysis result in limited impact on drug effects.



References:
[1] Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:10911-10916
[2] De Boer P, Van der Ark P, Kent J et al. Selective orexin-2 receptor antagonism improves sleep in insomnia disorder: A randomized, placebo-controlled, double-blind study. Presented at the Society of Biological Psychiatry (SOBP) 71st Annual Meeting, 12-14 May 2016, Atlanta, Georgia
[3] Bonaventure P, Shelton J, Yun S et al. Characterization of JNJ-42847922, a selective orexin-2 receptor antagonist, as a clinical candidate for the treatment of insomnia. J Pharmacol Exp Ther 2015;354(3):471-482
[4] NONMEM 7.2.0 Users Guide (1989-2011). Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds). Icon Development Solutions, Ellicott City, MD


Reference: PAGE 26 (2017) Abstr 7366 [www.page-meeting.org/?abstract=7366]
Poster: Drug/Disease modelling - CNS
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