STUDY OBJECTIVE: To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-â-cyclodextrin (HPâCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration.DESIGN: Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study.SETTING: Clinical research center.SUBJECTS: Healthy adult volunteers.INTERVENTION: Study 1: Subjects received HPâCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPâCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods.MEASUREMENTS AND MAIN RESULTS: Study 1: IV HPâCD-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 HPâCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPâCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPâCD-diclofenac (IV) to HPâCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPâCD-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 HPâCD-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 HPâCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml).CONCLUSIONS: Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPâCD-diclofenac compared with Voltarol and after IM administration of HPâCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPâCD-diclofenac was equivalent to IV administration of HPâCD-diclofenac and IV administration of Voltarol. Study 2: HPâCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPâCD-diclofenac. HPâCD-diclofenac was safe and well tolerated following IV and IM administration.
2-Hydroxypropyl-beta-cyclodextrin Administration, Oral