title: Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPβCD-diclofenac (Dyloject) compared with other diclofenac formulations.
abstract: 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.
  
  
  METHODS
  Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study.
  
  
  METHODS
  Clinical research center.
  
  
  METHODS
  Healthy adult volunteers.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Javelin Pharmaceuticals (now Hospira, Inc.), Cambridge, Massachusetts; The Leviathan Biopharma Group, Inc., Oncolupta, Inc., Newton, Massachusetts.
authors.forename: Fred
authors.initials: F
authors.lastname: Mermelstein
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hamilton
authors.forename: Curtis
authors.initials: C
authors.lastname: Wright
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lacouture
authors.forename: Atulkumar
authors.initials: A
authors.lastname: Ramaiya
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Carr
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000737:chemistry*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D008297:Male; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D047392:beta-Cyclodextrins; D004008:Diclofenac; D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: Dyloject; Voltarol; analgesia; diclofenac; hydroxypropyl-β-cyclodextrin; intramuscular; intravenous; oral; pharmacokinetics