This is a Phase 1, single dose, open-label study comparing the plasma pharmacokinetics and safety of RX0041-002 between subjects with hepatic impairment and age/gender/BMI-matched subjects with normal hepatic function.~DOSAGE~All subjects will receive a single treatment consisting of four (4) ml of a 4% solution of RX0041-002 (corresponding to 160 mg cocaine HCl) applied for 20 minutes to both nostrils using cotton pledgets. RX0041-002 Topical Solution (4%) will be provided by the Sponsor, supplied in 4 mL bottles. RX0041-002 Topical Solution contains citric acid, D&C Yellow No. 10, FD&C Green No. 3, sodium benzoate, and water.~DURATION OF STUDY~Total duration of study participation for each subject will be approximately 23 days not counting the variable 30 days for adverse event follow-up and resolution, if required. During that time, subjects will be screened for a maximum of 21 days and then confined to the study unit for approximately 45 hours for Day -1 evaluations, dosing (Day 1), blood sampling and safety assessments (Day 1-2).~NUMBER OF SUBJECTS~A sufficient number of subjects will be enrolled to complete 12 subjects with hepatic impairment, male or female volunteers ≥ 18 years of age. An additional 12 healthy, non-hepatically impaired, male or female volunteers will be enrolled as the comparator group. These subjects will be approximately age, body mass index (BMI) & gender-matched to the subjects with hepatic impairment. Hepatic impairment will be classified as moderate or severe and each grade/class will be defined according to Child-Pugh classification (Class B or C) . The liver impairment will be identified by a typical medical history, physical examination, coagulation and abnormal liver function tests (including bilirubin and albumin) at screening.~SAFETY PARAMETERS~Prior to enrollment (screening) and at the completion of the study, or at premature discontinuation, each subject will undergo a complete physical examination plus vital signs, clinical laboratory testing (serum chemistry, hematology, and urinalysis), and coagulation. In addition, subjects will be screened for inclusion with a 12-lead electrocardiogram, a urinary screen for drugs of abuse and blood tests for alcohol, serology tests for HIV antibody. Breath alcohol and urine drug screens will be repeated at check-in on Day -1 of the study. Females of child bearing potential will also be screened for inclusion with a serum pregnancy test. Urine pregnancy tests will also be performed at check-in on Day -1.~Each subject will be queried for the occurrence of adverse experiences following dosing and during blood sampling. Vital sign monitoring and recordings, will be obtained at baseline (pre-dose) (Day 1). Blood pressure, heart rate, respiratory rate and oral temperature will be taken and recorded every 15 minutes beginning immediately prior to dosing and for every 15 minutes for the first 60 minutes following pledget insertion. For the next 120 minutes (up to 180 minutes' post pledget insertion) vital sign recordings to include blood pressure, heart rate, respiratory rate and oral temperature measurements will be taken and recorded every 30 minutes to the 180 minute (3 Hour) post pledget insertion time point. Vital sign recordings to include blood pressure, heart rate, respiratory rate and oral temperature measurements will continue to be taken and recorded at hour 4, 6, 8, 10, 12, 16, 20, 24, 28 and 32 hours from time of pledget insertion or if necessary until the patient is clinically stable.~A nasal exam will be conducted, visually, pre-dose (Day 1) and at the end of study (Day 2) to determine if irritation is present at the application site following drug administration.~PHARMACOKINETIC BLOOD SAMPLING AND ANALYSIS~Pharmacokinetic blood samples will be drawn at the following times relative to the initiation of RX0041-002 dosing.~Subjects will be dosed and blood pharmacokinetic sampling will be conducted at 0 hour (pre-dose), and post dose at: 7 minutes, 15 minutes, 20 minutes, (immediately after pledget removal) 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, and 2, 3, 4, 6, 8, 10, 12, 24, 28 and 32 hours, based upon the beginning of dose application. For each time point, a minimum of 8 ml of blood will be sampled.~Total concentrations of cocaine and it major metabolites will be determined in all samples.
The primary objective of this study is to evaluate the potential effect of hepatic impairment on the systemic pharmacokinetics of RX0041-002 following single dose intranasal administration. The secondary objective is to evaluate the safety and tolerability of intranasal RX0041-002 in subjects with normal hepatic function and hepatic impairment.