Next Gen NRT pharmacokinetics and pharmacodynamics

Friends Research Institute, Inc., Baltimore MD

Investigators

Abstract

ABSTRACT: In the US alone, an estimated 540,000 people die prematurely each year from smoking or exposure to second-hand smoke, and another 8.6 million have serious illness caused by smoking. In addition, more than $96 billion is spent annually for medical expenditures to treat smoking associated diseases and another $97 billion per year in estimated lost productivity due to smoking.1 The most widely studied and used pharmacotherapies for smoking cessation are nicotine replacement therapies (NRT).2,8 However, the percentage of smokers who continue to abstain from smoking 12 months after using currently marketed NRTs is about 17% compared to 10% for placebo.3 Yet very little by way of new NRT have been introduced into the market, despite scientists' and clinicians' pleas for improved NRTs, specifically for a faster-acting NRT that resembles nicotine pharmacokinetics as produced by cigarette smoking.4- 6Thus, the current NRT smoking cessation pharmacotherapies (PK) have relatively poor efficacy, with more than 80% of the smoking cessation patients returning to smoking within a year. Additionally, the current non-nicotine pharmacotherapies have shown serious adverse events in patients, such as aggression and suicidal thoughts. Therefore, there is a significant unmet clinical need for a safe and efficacious smoking cessation therapy. Over 20 years ago a pioneer in smoking cessation defined the necessary attributes for a successful NRT as being: 1) the method should be safe and easy to use; 2) specific doses should be accurately and reproducibly delivered; 3) the pharmacokinetics should resemble those of cigarette smoking (T max range is 5 to 14 minutes).7 Yet none of the currently marketed NRTs meets all three criteria. We conducted a PK study under a Phase I STTR grant and demonstrated that a novel sublingual (SL) dosage form of nicotine has a rapid absorption into the plasma (T max = 17 minutes) as compared to a Tmax of 84 minutes with the COMMIT lozenge. A Pre-IND meeting was held with the FDA to discuss the development of the SL nicotine tablet as an OTC NRT product. The FDA laid out the regulatory developmental pathway. Using the FDA's advice as a guide, we filed a Strategic Alliances grant that proposed to complete the development of the sublingual nicotine tablet within three years. Although the grant was scored NIDA requested that we better characterize the rapid absorption of the SL tablet and its relationship to craving before we could re-submit an R01. Thus, we are proposing to compare the single dose PK and pharmacodynamics of the 4 mg SL tablet study to the 4 mg Nicorette lozenge to fulfill NIDA's request.