Safety, tolerability, and pharmacokinetics of ADL6906, a novel dual norepinephrine reuptake inhibitor and serotonin receptor antagonist

Abstract

ADL6906 is a novel dual norepinephrine reuptake inhibitor/serotonin (5-HT2) receptor antagonist with robust activity in a broad range of preclinical chronic and acute pain models. For example, in a neuropathic pain model (L5 spinal nerve ligation), tactile allodynia was significantly reversed at a dose that produced a maximum plasma concentration of approximately 300 ng/mL. Based on the preclinical analgesic efficacy, a phase 1 study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ADL6906 administered by mouth twice daily (BID) for 10 days. BID doses of 25 mg, 50 mg, 100 mg and 200 mg were studied in healthy volunteers (8 active, 2 placebo per cohort) with additional cohorts for evaluation in elderly (≥ 65 years old) and in fed/fasted states. Pharmacokinetic parameters for ADL6906 assessed after a single dose and at steady state included maximum plasma drug concentration (Cmax), time to Cmax (tmax), area under the concentration time curve (AUC) 0-∞, and AUC0-12. Safety endpoints included adverse events (AEs). ADL6906 exposure was approximately dose proportional and covered the efficacious exposure in the animal pain model with mean AUC0-∞ ranging from 6,022-24,732 h*ng/mL and mean Cmax ranging from 281-956 ng/mL at steady state. Compared with single dose data, accumulation at steady state was approximately 2-fold. Median tmax was achieved between 2 and 3 hours with mean t1/2 ranging from 17-19 hours. The elderly pharmacokinetic profile was similar to healthy volunteers. Food had no effect on exposure but resulted in moderately increased tmax (∼5 hours). The incidence of AEs was low and the great majority were mild. Headache was the most commonly reported AE. Of note, ADL6906 was well tolerated overall and at plasma levels equivalent to those that produced analgesic efficacy in preclinical models. Authors are Adolor Corporation employees or conducted the study.