Pharmacokinetics and brain σ1 receptor occupancy of MR309, a selective σ1 receptor antagonist.

AIMS: Preclinical studies of MR309, a selective sigma-1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report 2 studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309. METHODS: Steady-state PK of MR309 (400 mg once daily and 200 mg twice-daily [BID] for 10 days; EudraCT 2015-001818-99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017-000670-11 [positron emission tomography study]) were investigated in healthy volunteers. Positron emission tomography using the σ1R ligand [11 C]SA4503 was conducted at baseline, and 2 and 8 hours after a single dose of MR309 (200-800 mg). The relationship between brain σ1R occupancy and MR309 exposure was explored using data-driven model fitting. RESULTS: MR309 was well tolerated, brain σ1R occupancy ranged between 30.5 and 74.9% following single-dose MR309 (n = 7). MR309 BID provided a plasma PK profile with less fluctuation than once daily dosing (n = 16). MR309 200 mg BID yielded average steady state plasma concentrations between 2000 and 4000 ng/mL in the PK study, which corresponded to an estimated brain σ1R occupancy of 59-74%. CONCLUSION: MR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications.

Pharmacokinetics of Tramadol and Celecoxib in Japanese and Caucasian Subjects Following Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label Study.

BACKGROUND AND OBJECTIVES: Co-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class active pharmaceutical ingredient (API-API) co-crystal of rac-tramadol.HCl and celecoxib in a 1:1 molecular ratio (100 mg CTC: 44 mg rac-tramadol.HCl and 56 mg celecoxib). Tramadol and celecoxib pharmacokinetics are modified after CTC administration versus administration of reference products. This randomised, open-label, crossover, phase 1 study assessed CTC pharmacokinetics, dose proportionality, safety and tolerability in Japanese and Caucasian subjects. METHODS: CTC (100, 150 and 200 mg) was administered orally to healthy Japanese/Caucasian subjects. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were determined pre-dose and up to 48 h post-dose. Maximum observed plasma concentration (Cmax), and area under the plasma concentration-time curve from dosing to last measurable concentration (AUCt) and from dosing extrapolated to infinity (AUC∞) were evaluated. Dose proportionality was assessed in a dose-adjusted bioavailability analysis of variance and in a power model. Inter-cohort comparability of pharmacokinetic exposure was confirmed if the ratio (Japanese cohort/Caucasian cohort) of geometric least-squares means and corresponding 90% confidence intervals were 80-125%. Post hoc weight-adjusted comparability analyses were performed. Safety was assessed throughout. RESULTS: Sixty subjects (21 males/9 females per cohort) were randomised; 57 completed the study. Cohorts were age and BMI matched; there were expected inter-cohort weight differences. Exposure to each analyte increased in both cohorts with increasing CTC dose. Tramadol's pharmacokinetic exposure was comparable between cohorts after adjusting for body weight; the pharmacokinetic exposure of O-desmethyltramadol and celecoxib was increased in Japanese subjects. CONCLUSIONS: Differences in pharmacokinetics were not sufficient to suggest that CTC dose adjustment is required in Japanese subjects. CLINICAL TRIAL REGISTRATION: EudraCT: 2015-003071-29.

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study.

BACKGROUND AND AIMS: Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability. DESIGN: Open-label, randomized, five-way cross-over PK study. SETTING: Clinical trials facility (Croydon, UK). PARTICIPANTS: Thirty-eight healthy volunteers (age 20-54 years; 11 female). INTERVENTION AND COMPARATOR: Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone. MEASUREMENTS: Regular blood samples were taken, with high-frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration. FINDINGS: Mean peak concentration (Cmax ) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15-30 minutes (Tmax ). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47-51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3-minute intervals showed that comparable plasma naloxone concentrations would be anticipated. CONCLUSIONS: Concentrated 2 mg intranasal naloxone is well-absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post-dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.