(Part 1: Description) the proposed research, """"""""NDA-Enabling Phase I Lofexidine Program,"""""""" is aimed at characterizing the pharmacokinetic and clinical pharmacological profiles of lofexidine hydrochloride, an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short acting opioids. The research program consists of seven studies, each with a particular objective that will add to the overall understanding of the pharmacology of the investigational drug. The studies include evaluation of (1) effect of food on lofexidine's bioavailability, (2) pharmacokinetics in hepatically-impaired patients, (3) pharmacokinetics in renally-impaired patients, drug-drug pharmacokinetic interactions between lofexidine and (4) methadone, (5) naltrexone, and (6) buprenorphine (drugs for related indications that may be used concurrently in a clinical setting), and (7) a study of absolute bioavailability and mass balance of lofexidine. The studies will be conducted in normal, healthy volunteers or special populations (as in the case of the hepatic and renal impairment studies) and will employ use of liquid chromatography tandem mass spectrometry (LC/MS/MS) methodology to detect lofexidine hydrochloride parent molecule in the urine and plasma. Additionally, for one of the planned studies, tracer amounts (approximately 100 nCi) of radio-labeled 14C-lofexidine will be used in an oral dose and analyzed by Accelerated Mass Spectrometry in order to follow the plasma and excretion pharmacokinetics of parent drug, and to identify and quantify the excreted metabolites of lofexidine. The 14C-lofexidine dose and the appropriate AMS methods for specific identification and quantification of lofexidine metabolites is proposed to be developed as part of the research plan, which will allow identification and quantification of both lofexidine and its major metabolites in the plasma and urine. Quantification of lofexidine and/or its major metabolites over time in addition to observed tolerance and evaluation of other clinical parameters in each of the planned studies will add to the overall understanding of the pharmacokinetics and pharmacodynamics of lofexidine in the body. This information is needed to allow appropriate labeling of the product for its entrance to the US market. Furthermore, the planned research has been defined by the FDA as critical to complete the clinical pharmacology section requirements for a New Drug Application for lofexidine hydrochloride, approval of which will allow entrance of the first non-narcotic, non-addictive drug indicated for the treatment of opiate withdrawal to the US market.
(Project Summary, Part 2: Relevance) Opioid abuse and dependence is a serious and growing problem in the US, with an estimated 5.2 million nonmedical-related users of prescription opiate pain killers such as Lortab(R) and OxyContin(R) (SAMHSA, 2008), 1 million heroin addicts in the US (National Institutes of Health, 2006), and recent articles suggesting that abuse is spreading into rural and suburban areas (Archibold, 2009). There is an unmet medical need in the opioid-dependent population, with only two FDA-approved drugs (methadone and buprenorphine) currently available to treat opioid withdrawal. Both are opiate products that effectively operate as replacement or substitution therapies, have abuse potential and are themselves controlled substances. FDA approval of lofexidine hydrochloride will enable the entrance of the first non-narcotic, non-addictive product to the market for the treatment of opioid withdrawal, the first hurdle in recovery from opioid dependence. The planned research is required to understand how lofexidine works in the body so that appropriate dosing, meal requirements, the safety of combination with other treatment drugs, and safety considerations for patients with poor liver and kidney functions can be evaluated.