NovaDel Announces Positive Data from Pilot Pharmacokinetic Study Comparing Tizanidine Oral Spray to Zanaflex Tablets
Objectives of the Study
This Pilot Pharmacokinetic Study was designed to compare the PK profile of 2 mg, 4 mg and 8 mg Oral Spray (OS) doses of tizanidine hydrochloride to a 4 mg Zanaflex(R) (tizanidine hydrochloride) tablet dose in healthy male volunteers under fasting conditions. Assessment of the PD properties of tizanidine OS was made by administering the Digit Symbol Substitution Test (DSST) and measuring drowsiness levels via a self-assessment scale and changes in blood pressure and pulse rate associated with study drug administration. Safety and tolerability information was also collected.
Results of the Study
The data show substantially greater exposure to tizanidine from the OS formulations and earlier detectable plasma drug levels for OS doses versus the tablet (approximately 10 minutes and 17 minutes respectively, where p values ranged from 0.0002 to 0.0117). When dose normalized (to 4 mg), the bioavailability of the tizanidine OS doses were 2.04 to 3.49-fold greater than that of the 4 mg tablet.
The 2 mg oral spray and 4 mg tablet doses gave comparable results in the DSST test where positive scores were observed compared to baseline. There was an apparent decrease in the DSST scores after administration of the 4 mg and 8 mg OS study drugs. A decrease in the DSST score indicates a decrease in attention, perceptual speed, motor speed, visual processing and memory. Self-assessment of drowsiness indicated that subjects dosed with either the 4 mg or 8 mg OS assessed themselves as being "a bit more" or "much more" sleepy/drowsy than they were at baseline at a frequency comparable to that reported for the tablet. Reductions in blood pressure and pulse rate, recognized side effects of tizanidine, were observed with all doses of tizanidine OS and the tablet.
A total of 3 subjects had Adverse Events (AEs) of mild or moderate bradycardia and hypotension, which are well-recognized side effects of tizanidine, after the highest dose of tizanidine OS (8 mg). No subjects prematurely discontinued from the study due to AEs, and there were no Serious Adverse Events (SAEs) or deaths. No subjects reported any symptoms in the oral cavity. These results indicate that tizanidine OS is a well tolerated and safe based on the relatively small number of reported AEs and the absence of any SAEs both locally and systemically.
"These results further demonstrate the potential of our technology to rapidly deliver a variety of drugs across the oral mucosa" commented Mr. Steven Ratoff, NovaDel's Chairman of the Board and Interim President & Chief Executive Officer. "These results indicate that substantially greater bioavailability can be achieved with tizanidine in an oral spray form which may offer the opportunity for a product with an improved safety and side effect profile compared to tablets."
ABOUT THE STUDY
This was a single-center, 4-way crossover, open-label, dose-ranging, multiple-treatment PK study in healthy male volunteers 18 to 40 years old. There were 14 subjects planned; 14 subjects enrolled. Data from 14 subjects were evaluable for PK, pharmacodynamic and safety analyses. Treatments were separated by a period of 7 (+/- days). Blood samples (5.5 ml/sample) for PK evaluation were collected at each visit.
The OS test article used in this study has greater than 12 months physical and chemical stability and was supplied in 2 mg, 4 mg and 8 mg strengths. The tizanidine tablet was supplied from commercial sources as Zanaflex(R) from Acorda Therapeutics, Inc.
Pharmacokinetic: Maximum drug concentration (C(max)); time to maximum drug concentration (T(max)), time to detectable drug concentration (T(det)); elimination rate constant (K(e)); bioavailability (relative to the oral tablet); elimination half-life (t(1/2)); absorption t(1/2); area under the concentration time curve (AUC), including AUC(0-T), calculated from time 0 to the last non-zero concentration (C(T)), AUC(0-Infinity), calculated by extrapolation of AUC(0-T) to infinity by adding C(T)/K(e) to AUC(0-T); clearance (CL/F), clearance corrected for body weight (CL/F/kg); volume of distribution (Vd/F) and volume of distribution corrected for body weight (V(d)/F).
Pharmacodynamic: Digit Symbol Substitution Test (DSST), self-assessment of drowsiness, blood pressure (BP), and pulse rate.
Safety: Changes in physical examinations, including oral soft tissue examinations at after each lingual spray dosing, laboratory parameters, adverse events (AEs), and vital signs.
Spasticity affects over 500,000 people in the U.S. alone. Spasticity is not a disease, but rather a symptom of various neurological disorders, including, but not limited to multiple sclerosis (MS), spinal cord injury, stroke and cerebral palsy. These disorders cause a change in the balance of signals between the central nervous system and the muscles. This imbalance leads to involuntary tensing, stiffening and contracting of muscles. Tizanidine is the most widely prescribed treatment for spasticity with approximately 4 million prescriptions written annually.
ABOUT NOVADEL PHARMA
NovaDel Pharma Inc. is a specialty pharmaceutical company developing oral spray formulations for a broad range of marketed drugs. The Company's proprietary technology offers, in comparison to conventional oral dosage forms, the potential for faster absorption of drugs into the bloodstream leading to quicker onset of therapeutic effects and possibly reduced first pass liver metabolism, which may result in lower doses. Oral sprays eliminate the requirement for water or the need to swallow, potentially improving patient convenience and adherence.
NovaDel's oral spray technology is focused on addressing unmet medical needs for a broad array of existing and future pharmaceutical products. The Company's most advanced oral spray candidates target angina, nausea, insomnia, migraine headaches and disorders of the central nervous system. NovaDel plans to develop these and other products independently and through collaborative arrangements with pharmaceutical and biotechnology companies. To find out more about NovaDel Pharma Inc. (AMX: NVD), visit our website at www.novadel.com.
Except for historical information contained herein, this document may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements involve known and unknown risks and uncertainties that may cause the Company's actual results or outcomes to be materially different from those anticipated and discussed herein including, but not limited to, the successful completion of its pilot pharmacokinetic feasibility studies, the ability to develop products (independently and through collaborative arrangements), the ability to commercialize and obtain FDA and other regulatory approvals for products under development and the acceptance in the marketplace for oral spray products. Further, the Company operates in industries where securities may be volatile and may be influenced by regulatory and other factors beyond the Company's control. Important factors that the Company believes might cause such differences are discussed in the risk factors detailed in the Company's most recent Annual Report and Registration Statements, filed with the Securities and Exchange Commission. In assessing forward-looking statements contained herein, if any, the reader is urged to carefully read all cautionary statements contained in such filings. Zanaflex(R) is a registered trademark of Acorda Therapeutics, Inc.
NovaDel Pharma Inc.
Michael E. Spicer, 908-782-3431 ext. 2550
Chief Financial Officer
Posted: April 2008