P-041 - (Poster #41) Pharmacokinetics study comparing MR-107A-02 (novel fast-acting meloxicam formulation) 15mg tablet with meloxicam (Mobic®) 15mg in healthy adult male subjects

Meloxicam, a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits the cyclo-oxygenase -2 enzyme involved in the prostaglandin biosynthesis pathway, is effective in the management of moderate-to-severe pain. The pharmacokinetic profile of meloxicam demonstrates high oral bioavailability (89%) and extensive plasma protein binding ( >99%). The pharmacokinetics of meloxicam are linear over the entire dose range (7.5-30 mg) and remain unchanged from single to multiple dosing conditions. However, currently marketed oral meloxicam products release the drug slowly over an extended period, thus restricting their utility as an acute pain-reliever.

To overcome this challenge, a fast-releasing oral formulation, MR-107A-02, that facilitates a more rapid absorption than the currently available formulations of meloxicam has been developed. This formulation provides the additional benefit of being a more convenient route of administration compared to the intravenous (IV) formulation that has proven efficacy in the management of moderate-to-severe pain.

Purpose/Objectives:

The objective of this study was to compare the pharmacokinetics of MR-107A-02 tablet to reference product Mobic® (Meloxicam) tablet distributed by Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, USA, following a single, oral dose of 15 mg administered under fasting conditions.

Methods:

A single-dose, randomized, two-period, two-treatment, two sequence, crossover study was conducted at a single center in India. Healthy adult volunteers, aged 18 to 45 years, were randomized to receive a single, oral dose of 15 mg (1 × 15mg) of MR-107A-02 or Mobic® under fasting conditions. Blood samples were collected at pre-dose and at specific times after dosing and analyzed for meloxicam concentrations using liquid chromatography with tandem mass spectroscopy.

The maximum observed plasma concentration (C_max), area under the plasma concentration versus time curve to the last measurable concentration (AUC_t) and to infinity (AUC_i), partial area under the curve (pAUC) from time 0 to time 1-, 2-, 4- and 6-hours post-dosing, time to maximum observed plasma concentration (T_max), elimination rate constant (Kel), and apparent terminal elimination half-life (t_Half) were calculated using non-compartmental analysis. The 90% geometric confidence intervals of the ratio (A/B) of least-squares means from the ANOVA of the natural log transformed C_max, pAUCs, AUC_t and AUC_i were calculated to compare the two formulations.
The subjects were also monitored for safety through assessment of adverse events. The study was approved by an Institutional Review Board (IRB) and informed consent was obtained from all participants.

Results:

Of the 18 randomized (9 MR-107A-02, 9 Mobic®; all participants were Asian, males; mean [SD] age, 32 [6] years; mean [SD] weight, 57.8 [5.3] kg) subjects, 16 participants completed the study. Two participants withdrew from the study due to personal reasons.

MR-107A-02 demonstrated a more rapid absorption with a C_max value of 2734.342 (ng/mL) compared to Mobic® 1592.102 (ng/mL) and a significantly shorter T_max (hour) (0.958 vs 4.656). The geometric mean ratio of (A/B) 171.74 % with a corresponding 90% CI (159.92-184.44) fell completely outside the acceptable bioequivalence range (80-125%), demonstrating that MR-107A-02 delivered higher amounts of meloxicam to the systemic circulation at earlier time points. Comparison of pAUCs were also indicative of faster absorption from MR-107A-02 with approximately 23-, 10-, 3-, and 2-fold higher AUC_0-1h, AUC_0-2h, AUC_0-4h, and AUC_0-6h, respectively.

The comparison of AUC_t (ng/mL)*(hr) (MR-107A-02, 47442.139 vs Mobic® 41543.870) and AUC_i (ng/mL)*(hr) (MR-107A-02, 51878.350 vs Mobic® 45756.351) between the two formulations resulted in geometric mean ratios of AUC_t and AUC_i of 114.20% (90% CI [109.37-119.24]) and 113.38% (90% CI [108.02-119.00]) respectively, which fell well within the bioequivalent range. These findings revealed that MR-107A-02 and Mobic® were considered to be bioequivalent in terms of the overall extent of absorption.

Both formulations demonstrated nearly identical pharmacokinetic parameters in terms of Kel (1/hr) and t_Half (hr), indicating similar systemic clearance once absorbed.
There were no Adverse Events (AEs), or Serious Adverse Events (SAEs) reported throughout the study period.

Conclusions/Implications for future research and/or clinical care: MR-107A-02 demonstrated a more rapid absorption than Mobic®, as evidenced by a higher C_max, higher early pAUCs and shorter T_max values whereas AUC_t and AUC_i  remained essentially similar when administered under fasted conditions. These findings highlight the potential utility of oral MR-107A-02’s fast-releasing design to be used in an acute pain setting.