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ANESTHETIC PHARMACOLOGY

Pharmacokinetics and Bioavailability of Single-Dose Intranasal Hydromorphone Hydrochloride in Healthy Volunteers

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

*Department of Anesthesiology, University of Washington, Seattle; McKenzie Anesthesia Group, Springfield, Oregon; Intranasal Technology, Inc; Division of Otolaryngology-Head & Neck Surgery, University of Kentucky, A.B. Chandler Medical Center; 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 pharmacokinetics and absolute bioavailability of single doses of hydromorphone hydrochloride after administration of 1.0 and 2.0 mg of intranasal (IN) and 2.0 mg of IV hydromorphone hydrochloride. An open-label, randomized, three-way crossover study was conducted in 24 healthy volunteers (13 men and 11 women). IN doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1.0- and 2.0-mg doses, respectively. Blood samples were taken serially from 0 to 16 h after each dose. Plasma hydromorphone concentrations were determined by liquid chromatography-mass spectrometry-mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic varia-bles. Mean hydromorphone bioavailabilities and percent coefficient of variation of 52.4% (22.7) and 57.5% (18.6) were seen after the 1.0- and 2.0-mg IN doses, respectively. Median times to maximum concentration were 20 and 25 min for IN doses. Adverse events included somnolence and dizziness with all routes of administration and a bad taste after IN doses. Dose proportionality for the 1.0- and 2.0-mg IN doses was observed. IN hydromorphone hydrochloride met the minimum requirements for safety and demonstrated rapid nasal drug absorption and clinically relevant bioavailability. Results support further development of this novel hydromorphone hydrochloride nasal spray.

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

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