P-045 - (Poster #45) Steady-state pharmacokinetic properties of a sublingual formulation of cyclobenzaprine (CBP) HCl (TNX-102 SL): comparison to simulations of oral immediate-release CBP

Background: TNX-102 SL is a sublingual formulation of cyclobenzaprine (CBP) designed for bedtime administration and is under development for the treatment of fibromyalgia (FM) and acute stress disorder (ASD). Compared to oral immediate-release (IR) CBP, TNX-102 SL provides rapid transmucosal absorption, increased bioavailability, and reduced formation of the long half-life active metabolite norcyclobenzaprine (nCBP) by partially bypassing first-pass hepatic metabolism. CBP exhibits antagonism at the 5-HT2A serotonergic, α1-adrenergic, M1-muscarinic acetylcholine, and H1-histaminergic receptors, each implicated in sleep regulation. In contrast, nCBP may interfere with CBP’s receptor activity and disrupt sleep through potent inhibition of the norepinephrine transporter (NET). Oral CBP has demonstrated poor tolerability in clinical studies, potentially due to nCBP accumulation. Previous Phase 1 pharmacokinetic (PK) studies (unpublished) indicate that TNX-102 SL results in lower systemic exposure to nCBP relative to oral IR CBP.

Purpose/Objectives: This post hoc analysis compares the steady-state PK profile of TNX-102 SL 5.6 mg with a simulated PK profile of oral IR CBP, focusing on plasma concentrations of CBP and nCBP.

Methods:

As part of a 60 healthy subject PK study, 30 participants were randomized to TNX-102 SL (ages 18-75) for 20 days of dosing. Plasma samples were used to assess PK parameters. Safety was assessed by adverse events (AEs), Columbia-Suicide Severity Rating Scale (C-SSRS), physical exam, vital signs, ECGs, and laboratory parameters.

In order to allow a comparison of the exposures of CBP and nCBP between sublingual CBP HCl and oral IR CBP HCl, concentration-time courses of CBP and nCBP during multiple dosing at steady-state were simulated for multiple dosing by nonparametric superposition from observed concentration-time profiles after single-dose administration of sublingual CBP HCl 2.8 mg or oral IR CBP 5 mg. The simulations were performed under the assumption of linear pharmacokinetics as previously reported for IR CBP HCl and provided average concentration-time profiles at steady-state for oral IR CBP HCl at daily doses of 5 mg and 10 mg and sublingual CBP HCL at 5.6 mg.

Results:

On Day 20, mean C_max and AUC at steady-state for CBP were 11.2 ng/mL and 175 h*ng/mL, respectively, for TNX-102 SL, with a T_max of 5 h. For nCBP, mean C_max and AUC were 10 ng/mL and 205 h*ng/mL, respectively.

No unexpected AEs were observed with TNX-102 SL. Most of the AEs reported were mild in severity, and the majority of AEs resolved without treatment. The most frequent AEs reported in the TNX-102 SL group were mild and transient oral administration site reactions, eg, tongue or oral numbness.

A simulation of oral IR CBP was created using data from a prior Phase 1 PK study. Comparison of these simulations with the TNX-102 SL PK profiles in this study suggests that compared to daily TNX-102 SL 5.6 mg, 10 mg once-daily oral IR CBP results in only a 40% higher AUC for CBP but a 128% higher AUC for nCBP. This result implies a higher ratio of CBP to nCBP exposure when CBP is administered by the SL rather than the oral route.

Conclusions/Implications for future research and/or clinical care:

Daily administration of TNX-102 SL 5.6 mg for 20 days was well-tolerated in healthy subjects.

For the intended therapeutic daily bedtime administration, these data show that during typical hours of sleep (0-8 h post-dose), CBP steady-state concentration and AUC were higher than nCBP post-TNX-102 SL administration, optimizing the effects of CBP on the sleeping brain. In contrast, simulation of oral IR CBP predicted that steady-state concentration and AUC were higher for nCBP than CBP during sleep. It is reasonable to expect that during waking hours (8-24 h post-dose), TNX-102 SL provides lower CBP levels than nCBP. The dynamic changes in CBP over 24 h are believed to optimize the effects on the brain, and these changes are magnified by the predicted occupancy of relevant receptors, since CBP has higher affinities for 5HT2A, α1, H1 and M1 receptors than nCBP. In contrast, nCBP has higher affinity for the norepinephrine (NE) transporter, which would be expected to impair sleep due to higher synaptic NE availability during the period in which optimal sleep quality is associated with lower NE activity. Together, these data support the use of TNX-102 SL as a potential chronic bedtime treatment for fibromyalgia and ASD.

Supported by: Tonix Pharmaceuticals.