(W0930-02-09) Toxicokinetics of MEB-1170, a mu-Opioid Receptor Agonist, in Dogs in a 28-Day Oral Toxicity Study

Purpose: To assess the toxicokinetics (TK) of MEB-1170 and its metabolite MEB-373 following once-daily oral administration to dogs. MEB-1170, a mu-opioid receptor (MOR) agonist, is being developed as a novel analgesic for the treatment of pain and the prevention of opioid use disorder. MEB-1170 successfully completed a First in Human study with the completion of a single ascending dose (SAD) in healthy Human volunteers with no drug related adverse events (https://classic.clinicaltrials. gov). In preclinical models, Tounge, et al., (2018) reported that MEB-1170 (5 and 20 mg/kg) had longer duration of action than morphine (1 and 5 mg/kg) and TRV-130 (0.3 and 1.2 mg/kg) and did not impact respiratory function or cause sedation or constipation.

Methods: The study consisted of four groups of male and female dogs (N = 5 animals/sex/group).  MEB-1170 was administered by oral gavage at dose levels of 0, 3, 15 and 60 mg/kg/day to Groups 1, 2, 3 and 4, respectively, for 28 consecutive days. Blood samples were collected at predetermined times from all dogs on Days 1 and 28 and were used for measuring MEB-1170 and its metabolite MEB-373 plasma concentrations by validated HPLC/MS/MS assays. The TK parameters were determined by model independent methods.

Results: MEB-1170 Day 1 TK: Following a single oral administration of MEB-1170 at 3, 15 and 60 mg/kg to dogs, MEB-1170 was absorbed into the systemic circulation with T_max values ranging from 0.250 to 1.50 h. Systemic exposure of MEB-1170 (C_max and AUC_(0-24)) increased with MEB-1170 dose in an approximately dose proportional manner. In males, mean C_max values were 91.0, 749 and 1,980 ng/mL and mean AUC_(0-24) values were 276, 1,140 and 2,510 ng·h/mL for MEB-1170 doses of 3, 15 and 60 mg/kg/day, respectively. Corresponding mean C_max values in females were 191, 941 and 3,210 ng/mL and mean AUC_(0-24) values were 299, 1,140 and 3,810 ng·h/mL (Table 1). There were no gender-related TK exposure differences. MEB-1170 Day 28 TK Day 28 MEB-1170 T_max values ranged from 0.250 to 2.00 h postdose. Systemic exposure of MEB-1170 increased with MEB-1170 dose in a greater than proportional manner for males and females. In males, mean C_max values were 190, 1,510 and 5,180 ng/mL and mean AUC_(0-24) values were 766, 5,730 and 31,000 ng·h/mL for MEB-1170 doses of 3, 15 and 60 mg/kg/day, respectively. Corresponding mean C_max values in females were 204, 1,820 and 5,620 ng/mL and mean AUC_(0-24) values were 580, 3,970 and 30,500 ng·h/mL (Table 1). There were no gender-related TK exposure differences. TK exposure to MEB-1170 was greater than Day 1 exposure for both sexes. MEB-373 Day 1 TK. Following a single oral administration of MEB-1170 at 3, 15 and 60 mg/kg to dogs, the metabolite MEB-373 was measurable in systemic circulation with T_max values ranging from 0.250 to 2.00 h. Systemic exposure of MEB‑373 increased with MEB-1170 dose in a dose proportional manner. In males, mean C_max values were 1.80, 31.9 and 51.9 ng/mL and mean AUC_(0-24) values were 2.61, 41.3 and 67.8 ng·h/mL for MEB-1170 doses of 3, 15 and 60 mg/kg/day, respectively. Corresponding mean C_max values in females were 3.83, 25.3 and 101 ng/mL and mean AUC_(0-24) values were 3.53, 27.2 and 150 ng·h/mL (Table 1). There were no gender-related TK exposure differences. Systemic exposure to MEB-373 was low for both sexes (~0.9% to 4.3% of MEB‑1170). MEB-373 Day 28 TK: Day 28 MEB-373 T_max values were variable and ranged from 0.250 to 2.00 h. Systemic exposure of MEB-373 increased with MEB‑1170 dose in a greater than proportional manner for males and females.  In males, mean C_max values were 8.54, 80.9 and 262 ng/mL and mean AUC_(0-24) values were 44.8, 649 and 2,300 ng·h/mL for MEB-1170 doses of 3, 15 and 60 mg/kg/day, respectively.  Corresponding mean C_max values in females were 5.13, 54.4 and 341 ng/mL and mean AUC_(0-24) values were 22.8, 294 and 2,960 ng·h/mL for MEB-1170 doses of 6, 20 and 60 mg/kg/day, respectively (Table 1).  There were no consistent gender-related exposure differences.  Day 28 TK exposure to MEB-373 was greater than Day 1 exposure for both sexes.  Systemic exposure to MEB-373 was low for both sexes (~3.0% to 11.2% of MEB‑1170).

Conclusion: The systemic exposure to MEB-1170 and MEB-373 was determined in male and female dogs following daily oral administration of 3, 15 and 60 mg/kg/day MEB-1170 for 28 consecutive days. There were no gender‑related exposure differences for MEB-1170 and MEB-373. Systemic exposure of MEB-1170 and MEB-373 increased with MEB-1170 dose in an approximately dose proportional manner on Day 1 and increased with MEB-1170 dose in a greater than proportional manner on Day 28. Day 28 TK exposure to MEB-1170 and MEB-373 was greater than Day 1 exposure. Systemic exposure to MEB-373 was low on Days 1 and 28 (~0.9% to 11.2% of MEB‑1170).

References: B Tounge, S Bayoumy, R Besthof, S Dax, L Kuo, and J Barrett (2018). Novel, highly biased mu opioid receptor compounds minus side effects for the treatment of pain. Volume 19, ISSUE 3, SUPPLEMENT, S82, March 2018.
A Phase I, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEB-1170 in Healthy Subjects. https://classic.clinicaltrials.gov/ct2/show/NCT05748119

TK Table

TK Profiles

TK Profiles