• Fred Mermelstein, Douglas A Hamilton, Curtis Wright, Peter G Lacouture, Atulkumar Ramaiya, and Daniel B Carr.
• Javelin Pharmaceuticals (now Hospira, Inc.), Cambridge, Massachusetts; The Leviathan Biopharma Group, Inc., Oncolupta, Inc., Newton, Massachusetts.
• Pharmacotherapy. 2013 Oct 1;33(10):1012-21.

Study ObjectiveTo evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration.DesignStudy 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study.SettingClinical research center.SubjectsHealthy adult volunteers.InterventionStudy 1: Subjects received HPβCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPβCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods.Measurements And Main ResultsStudy 1: IV HPβCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPβCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPβCD-diclofenac (IV) to HPβCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPβCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPβCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml).ConclusionsStudy 1: Bioavailability in terms of AUC after IV administration was equivalent for HPβCD-diclofenac compared with Voltarol and after IM administration of HPβCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPβCD-diclofenac was equivalent to IV administration of HPβCD-diclofenac and IV administration of Voltarol. Study 2: HPβCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPβCD-diclofenac. HPβCD-diclofenac was safe and well tolerated following IV and IM administration.© 2013 Hospira, Inc. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of the American College of Clinical Pharmacy.

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