Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HP β CD ‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

Study Objective To evaluate single‐ and repeated‐dose pharmacokinetics ( PK ) and dose proportionality of hydroxypropyl‐β‐cyclodextrin ( HP β CD) ‐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 HP β CD ‐diclofenac and Voltarol, IV and IM , with a 5‐day washout between treatment periods. Study 2: Subjects received two doses of IV HP β CD ‐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 HPβCD‐diclofenac had a higher peak plasma concentration (C max ) and earlier time to reach maximum plasma concentration (T max ), but equivalent plasma exposure (area under the curve from time zero to t [AUC 0–t ]) to IV Voltarol. The geometric mean ratio of HPβCD‐diclofenac (IV) to Voltarol (IV) for AUC 0–t was 106.27%. The geometric mean ratio of HPβCD‐diclofenac (IM) to Voltarol (IM) for AUC 0–t was 110.91%. The geometric mean ratio of HPβCD‐diclofenac (IV) to HPβCD‐diclofenac (IM) for AUC 0–t was 101.25%. The geometric mean ratio of HPβCD‐diclofenac (IM) to Voltarol (IV) for AUC 0–t was 104.96%. Study 2: C max 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 ). Conclusions Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HP β CD ‐diclofenac compared with Voltarol and after IM administration of HP β CD ‐diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HP β CD ‐diclofenac was equivalent to IV administration of HP β CD ‐diclofenac and IV administration of Voltarol. Study 2: HP β CD ‐diclofenac showed dose proportionality after single‐ and multiple‐dose administration and no accumulation of HP β CD ‐diclofenac. HP β CD ‐diclofenac was safe and well tolerated following IV and IM administration.