Single-Dose and Multiple-Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD-Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

• Published in: Pharmacotherapy 2013-10, Vol.33 (10), p.1012-1021
• Main Authors: Mermelstein, Fred, Hamilton, Douglas A., Wright, Curtis, Lacouture, Peter G., Ramaiya, Atulkumar, Carr, Daniel B.
• Format: Article
• Language: English
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Adult; analgesia; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Area Under Curve; beta-Cyclodextrins - chemistry; Biological and medical sciences; Biological Availability; Cross-Over Studies; diclofenac; Diclofenac - administration & dosage; Diclofenac - adverse effects; Diclofenac - pharmacokinetics; Dose-Response Relationship, Drug; Dyloject; Excipients - chemistry; Female; Humans; hydroxypropyl-β-cyclodextrin; Infusions, Intravenous; Injections, Intramuscular; intramuscular; intravenous; Male; Medical sciences; oral; pharmacokinetics; Pharmacology. Drug treatments; Voltarol
• ISSN: 0277-0008; 1875-9114
• DOI: 10.1002/phar.1304

Study Objective To 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. 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 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 Results Study 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). Conclusions Study 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.