Anita C. Rudy

Bioavailability and Pharmacokinetics of Lorazepam after Intranasal, Intravenous, and Intramuscular Administration

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1‐week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7 (11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration‐time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.

Hydromorphone transfer into breast milk after intranasal administration.

Study Objectives. To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model.

A Multiple-Dose Phase I Study of Intranasal Hydromorphone Hydrochloride in Healthy Volunteers

We evaluated the pharmacokinetics, tolerability, and safety of 1 and 2 mg of intranasal hydromorphone hydrochloride in an open-label, single- and multiple-dose study. This Phase I study was conducted in 24 healthy volunteers (13 men and 11 women). Intranasal doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1- and 2-mg doses, respectively. Venous blood samples were taken serially from 0 to 12 h after the first single dose and the last (seventh) multiple dose. Plasma hydromorphone concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic variables. After 7 intranasal doses of 1 and 2 mg (once every 6 h), mean ± sd peak plasma concentrations of 2.8 ± 0.7 ng/mL and 5.3 ± 2.3 ng/mL, respectively, were observed. The median time to peak concentration was 20 min for both single and multiple doses. Dose proportionality was observed for the 1- and 2-mg doses. Adverse events included somnolence, dizziness, and bad taste after dose administration. Intranasal hydromorphone hydrochloride was well tolerated and demonstrated rapid nasal drug absorption and predictable accumulation. These results support clinical investigation of hydromorphone hydrochloride nasal spray for use as an alternative to oral and IM administration.

Effect of fluticasone propionate nasal spray on bioavailability of intranasal hydromorphone hydrochloride in patients with allergic rhinitis.

Study Objective. To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single‐dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis.

Bioavailability and Pharmacokinetics of Intranasal Hydromorphone in Patients Experiencing Vasomotor Rhinitis

Background and objectiveNarcotic analgesics such as hydromorphone undergo an extensive first-pass effect resulting in a low systemic bioavailability following oral administration. Alternative dosing routes, such as rectal and intranasal (IN) routes, have been suggested as options for oral or intravenous administration. Rhinitis and pharmacological agents used for treatment are considered factors that could alter the rate and extent of absorption of drugs administered by the nasal route. The purpose of this study was to evaluate the pharmacokinetics of intranasal hydromorphone hydrochloride (HCl) in patients with vasomotor rhinitis.MethodsTen patients completed the randomised, three-way crossover study. During the three treatment periods, a single dose of hydromorphone HCl 2.0mg was administered via intravenous infusion (treatment A) and the intranasal route without (treatment B) or with (treatment C) vasoconstrictor pretreatment for rhinitis. Blood samples were collected serially from 0 to 16 hours. Noncompartmental methods were used to determine pharmacokinetic parameters.ResultsMaximum plasma concentrations were 3.69 and 3.38 μg/L for treatments B and C, respectively. Mean (% coefficient of variation) bioavailability of intranasal hydromorphone was 54.4% (34.8) and 59.8% (22.1) with and without pretreatment, respectively. Pretreatment of rhinitis did not significantly affect the rate or extent of absorption of hydromorphone in this study. There was not a significant difference in bioavailability between treated and untreated rhinitis.ConclusionsThis study found intranasal administration of hydromorphone in patients experiencing vasomotor rhinitis had acceptable bioavailability and a pharmacokinetic profile comparable to previous studies. These data support further investigation of this single-dose delivery system for clinical use.

A multicenter, open-label, exploratory dose-ranging trial of intranasal hydromorphone for managing acute pain from traumatic injury.

UNLABELLED We conducted a prospective multicenter, open-label, escalating dose-range trial to compare, across patients, single intranasal doses (2, 4, 6, 8, and 10 mg) of hydromorphone HCl in the treatment of acute trauma pain The main outcome measure of pain-intensity reduction was derived from serial Numerical Pain-Rating Scores and calculated as the summed pain-intensity difference over 3 hours (SPID 3). Nasal examinations, vital signs, and adverse events were reported as safety outcomes. The mean decrease in pain intensity from baseline to 30 minutes was 39 to 44% for the 4-, 6-, 8- and 10-mg doses (n = 19, 33, 28, and 19 per group) and only 24% reduction for the 2-mg dose (n = 14). SPID 3 for the 2-mg dose was 40 to 50% below all other doses. There were no clinically meaningful changes in vital signs or nasal examinations. Adverse events (nausea, vomiting, pruritus, oxygen desaturation, bad taste, dizziness) were of mild to moderate intensity, increased with dose, and expected, based on route of administration and opioid pharmacology. Intranasal hydromorphone provides a component of rapid pain relief in the care of emergency department patients suffering from acute trauma pain. PERSPECTIVE This article presents a pilot dose-ranging study of intranasally administered hydromorphone, administered in the emergency department to patients suffering from acute trauma pain. This study demonstrates research success in this setting and noninjection-based delivery and certain doses of intranasal hydromorphone may be effective in treating acute trauma pain.

240) A pharmacokinetic profile of intranasal hydromorphone in emergency room trauma patients

Intranasal hydromorphone HCl is under development for the management of moderate to severe trauma pain. An element of this investigation was to assess plasma concentrations at near peak times, at the end of a typical dosing interval and across a range of doses being evaluated for relative clinical efficacy and tolerability. Intranasal administration of hydromorphone with a sprayer configured to deliver 2, 4, 6, 8 or 10mg of hydromorphone in 100 L of solution was studied in patients with pain 5 on a 0-10 scale and were evaluated as candidates for opioid treatment. Blood was obtained at baseline and a single dose of intranasal hydromorphone administered. Samples were collected at 30, 60 and 180 minutes following dosing then assayed using LC/MS/MS for plasma hydromorphone concentrations. Patients (n 113) were dosed with 2mg (n 14), 4mg (n 19), 6mg (n 33), 8mg (n 28) or 10mg (n 19) of intranasal hydromorphone. Analysis of plasma hydromorphone demonstrated a dose-related increase at most timepoints. The maximum measured concentration was observed at 30 minutes (mean 2.22ng/mL with 2mg, 4.26ng/mL with 4mg, 5.04ng/mL with 6mg, 6.21ng/mL with 8mg and 7.14ng/mL with 10mg). Concentrations observed following 2mg intranasal doses were similar to those seen for 2mg doses in healthy volunteers. Therapeutic concentrations of hydromorphone in acute pain approximate 4ng/mL. With this intranasal administration at the 30 minute timepoint, 2mg was at or above this concentration in 7% of patients, in 42% of patients with 4mg, in 63% of patients with 6mg, in 81% of patients with 8mg and in 95% of patients with 10mg indicating potential for rapid pain relief. We conclude that for trauma patients presenting to the ER, intranasal administration of this product resulted in rapid absorption of hydromorphone into the plasma. These plasma hydromorphone concentrations are consistent with analgesic concentrations reported in the literature. Supported by Intranasal Therapeutics, Inc.