(T1230-02-11) Toxicokinetics of MEB-1170, a mu-Opioid Receptor Agonist, in Rats 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 rats in a 28-Day toxicity study. 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 TK portion of the rat study included 4 groups; Group 5 (vehicle) consisted of 3 animals/sex and Groups 6 through 8 consisted of 9 animals/sex.  MEB-1170 was administered by oral gavage at 0, 6, 20 and 60 mg/kg/day to Groups 5, 6, 7 and 8, respectively, for 28 consecutive days.  Blood samples for TK analysis were collected at predetermined times and plasma was analyzed for MEB-1170 and its metabolite MEB-373 by validated HPLC-MS/MS assays. The TK parameters were determined by model independent methods.  MEB-373 plasma concentrations were mostly BQL at 6 mg/kg/day for males and females on Day 1 and males on Day 28: therefore, the data for MEB-373 at 6 mg/kg/day are limited to females only on Day 28.

Results: MEB-1170 Day 1 TK: Following a single oral administration of MEB-1170 to male and female rats, MEB-1170 was absorbed into the systemic circulation with Tmax values ranging from 0.250 to 4.00 h postdose. Day 1MEB-1170 systemic exposure (C_max and AUC_(0-24)) increased as a function of dose in approximately a more than dose proportional manner and was similar in both sexes (See Table 1 and the C_max and AUC_(0-24) values listed below). In males, C_max values were 32.7, 95.7 and 579 ng/mL and the AUC_(0-24) values were 147, 686 and 4,020 ng·h/mL for MEB-1170 doses of 6, 20 and 60 mg/kg/day, respectively. Corresponding C_max values in females were 35.0, 117 and 496 ng/mL and AUC_(0-24) values were 160, 895 and 4,640 ng·h/mL. MEB-1170 Day 28 TK: Day 28 MEB-1170 systemic exposure was higher than that of Day 1, increased as a function of dose in approximately a more than dose proportional manner and was similar in both sexes (Table 1). In males, MEB-1170 C_max values were 54.3, 178 and 731 ng/mL and AUC_(0-24)values were 318, 1,510 and 6,580 ng·h/mL for MEB-1170 doses of 6, 20 and 60 mg/kg/day, respectively. Corresponding C_max values in females were 85.2, 188 and 1,150 ng/mL and AUC_(0-24) values were 373, 1,390 and 7,500 ng·h/mL._. MEB-373 Day 1 TK: Following a single oral administration of MEB-1170 at 20 and 60 mg/kg to male and female rats, the metabolite MEB-373 was measurable in systemic circulation with T_max value of 4.00 h postdose (Table 1). Day 1 MEB-373 systemic exposure was low (~0.01% to 0.08% of MEB‑1170 exposure), increased as a function of MEB-1170 dose in approximately a more than dose proportional manner and was similar, and lower in males than females (Table 1). In males, MEB-373 C_max values were 1.66 and 27.4 ng/mL and AUC_(0-24) values were 7.55 and 167 ng·h/mL for MEB-1170 doses of 20 and 60 mg/kg/day, respectively. Corresponding C_max values in females were 7.98 and 37.8 ng/mL and AUC_(0-24) values were 5.6 and 374 ng·h/mL. MEB-373 Day 28 TK: Day 28 MEB-373 systemic exposure was low (~0.03% to 0.1% of MEB‑1170 exposure), higher than that of Day 1 exposure, increased as a function of MEB-1170 dose in approximately a more than dose proportional manner, and lower in males than females (Table 1). In males, MEB-373 C_max values were 6.17 and 46.0 ng/mL and the AUC_(0-24)values were 57.8 and 443 ng·h/mL for MEB-1170 doses of 20 and 60 mg/kg/day, respectively. Corresponding C_max values in females were 4.68, 11.3 and 89.4 ng/mL and AUC_(0-24) values were 10.9, 106 and 771 ng·h/mL for MEB-1170 doses of 6, 20 and 60 mg/kg/day, respectively.

Conclusion: The exposure for MEB-1170 and its metabolite MEB-373 increased as a function of MEB-1170 dose and was higher on Day 28 than that on Day 1. MEB-1170 exposure did not appear to exhibit TK-sex-related differences, while MEB-373 exposure was lower in females than that in males. MEB-373 exposure was low and ranged from ~1.1 to 10.3%% of MEB‑1170 exposure.

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