Pharmacokinetics of Diclofenac and Hydroxypropyl-ß-Cyclodextrin (HPßCD) Following Administration of Injectable HPßCD-Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment.

Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl-ß-cyclodextrin (HPßCD) following administration of the injectable NSAID HPßCD-diclofenac; and (2) the PK of HPßCD following administration of HPßCD-diclofenac and intravenous itraconazole formulated with HPßCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half-life, t½ ) and renal function. HPßCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½ . There were no significant differences in diclofenac or HPßCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPßCD in healthy subjects following HPßCD-diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPßCD-diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).