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AMBULATORY ANESTHESIA

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

Anita C. Rudy, PhD^*, Barbara A. Coda, MD^,, Sanford M. Archer, MD, and Daniel P. Wermeling, PharmD^*,||

*Intranasal Technology, Inc., Lexington, Kentucky; Department of Anesthesiology, University of Washington, Seattle, Washington; McKenzie Anesthesia Group, Springfield, Oregon; Division of Otolaryngology-Head &Neck Surgery, University of Kentucky A. B. Chandler Medical Center, Lexington, Kentucky; and ||University of Kentucky College of Pharmacy, Lexington, Kentucky

Address correspondence and reprint requests to Daniel P. Wermeling, PharmD, Intranasal Technology, Inc., Coldstream Research Campus, 1513 Bull Lea Blvd., Lexington, KY 40511-1200. Address e-mail to info{at}intranasal.com

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.

IMPLICATIONS: Pharmacokinetics were determined for multiple doses of intranasal hydromorphone hydrochloride in healthy volunteers. Rapid absorption and predictable accumulation and pharmacokinetics support the investigation of hydromorphone hydrochloride nasal spray as a therapeutic alternative to oral and IM administration.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999