Pharmacokinetics and Safety of a Diclofenac Sodium 75 mg/1 mL Solution (Akis®/Dicloin®) Administered as a Single Intravenous Bolus Injection in Healthy Men and Women

Eur J Drug Metab Pharmacokinet. 2019 Oct;44(5):681-689. doi: 10.1007/s13318-019-00558-8.

Abstract

Background: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-β-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration.

Objectives: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products.

Methods: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation.

Results: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus.

Conclusions: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin / administration & dosage
  • 2-Hydroxypropyl-beta-cyclodextrin / adverse effects
  • 2-Hydroxypropyl-beta-cyclodextrin / pharmacokinetics
  • Adolescent
  • Adult
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*
  • Area Under Curve
  • Biological Availability
  • Cross-Over Studies
  • Diclofenac / administration & dosage
  • Diclofenac / adverse effects*
  • Diclofenac / pharmacokinetics*
  • Female
  • Humans
  • Injections, Intramuscular
  • Injections, Intravenous / methods
  • Middle Aged
  • Young Adult

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Diclofenac
  • 2-Hydroxypropyl-beta-cyclodextrin