A Phase-1 Study Comparing the Pharmacokinetics of Intranasal RX0041-002 in Subjects With Severe Renal Impairment and Subjects With Normal Renal Function

Brief Summary

Detailed Description

The primary objective of this study is to evaluate the potential effect of renal impairment on the systemic pharmacokinetics of acute Intranasal RX0041-002. The secondary objective is to evaluate the safety and tolerability of acute intranasal RX0041-002 in subjects with normal renal function and severe renal impairment. 2 INVESTIGATOR/STUDY SITE The study will be conducted at Comprehensive Clinical Research in Berlin, New Jersey. The principal investigator will be Dr. David Hassman. Institutional review will be performed by Chesapeake Institutional Review Board.. 3 BACKGROUND Cocaine Hydrochloride Topical Solution (4%) is currently available for the induction of local (topical) anesthesia of accessible mucous membranes of the oral, laryngeal and nasal cavities (DESI product). Pennsylvania Pain Specialists (PPS) are seeking FDA approval for RX0041-002 as a topical anesthetic for diagnostic and surgical procedures in the nasal cavity. Cocaine is a naturally-derived local anesthetic with a long history of use. Like other structurally-related local anesthetics, cocaine produces direct effects on cell membranes. Cocaine blocks sodium channel activity and thus prevents the generation and conduction of nerve impulses in electrically active cells. Cocaine also has vasoconstriction properties which for surgical or diagnostic procedures of the mucous membranes of the nasal cavities decreases operative bleeding and improves surgical visualization. The therapeutic use of cocaine hydrochloride, 4% solution topically applied to the nasal septum for local anesthesia is reported in the public clinical literature but has never received official FDA approval for this indication. It has been used in surgical procedures involving the nose, throat, larynx and lower respiratory passages because blood loss from these highly vascularized areas can be considerable and may also obscure the operative field. The pharmacokinetics of cocaine administered via nasal absorption has been reported in the literature. However, regardless of the route of administration, several studies have shown that cocaine has a plasma half-life of 0.5-1.5 h, an apparent volume of distribution of 2-3 L/kg, and an apparent systemic clearance of ≈2 L/min. Only 1-5% of cocaine is cleared unmetabolized in urine, where it may be detected for only 3-6 h after use. The primary pathway of cocaine elimination is by hydrolysis of its two ester groups to form the two major inactive metabolites, ecgonine methyl ester (EME) and benzoylecgonine (BE), with half-lives of approximately 4 and 6 h, respectively. These compounds constitute over 80% of cocaine's metabolites and are detected in urine for 14-60 h after cocaine administration. Norcocaine, a minor but active metabolite, is formed by cytochrome P450 (CYP 3A4) mediated N-demethylation of cocaine. However, only 2% - 6% of cocaine is metabolized to norcocaine in humans. The present study is being conducted to evaluate the potential effects of renal impairment on the pharmacokinetics of cocaine, its major metabolites and the active metabolite (norcocaine) after (4%) intranasal cocaine HCl topical administration, at the typical clinical dose of 160 mg. 4 SUMMARY OF DRUG INFORMATION RX0041-002 (Cocaine HCl, USP) is a crystalline, granular, or powder substance having a saline, slightly bitter taste that numbs tongue and lips. Each mL of RX0041-002 Topical Solution contains Cocaine HCl 40 mg (4%) as an aqueous solution. 5 SUBJECT POPULATION The subject population for this study will include male and female adults (≥ 18 years). A sufficient number of subjects will be enrolled to complete 8 subjects with severe renal impairment and 8 subjects with normal renal function. The subjects with normal renal function will be selected in order to match the subjects with renal impairment in terms of age, sex and BMI. For assignment to the treatment groups, severe renal impairment will be defined as an eGFR of 15-29 mL/min/1.73m2. Normal renal function will be defined as an eGFR ≥ 90 mL/min/1.73m2.

Primary Outcomes