Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Abstract

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‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD 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. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½. There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐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 HPβCD‐diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

“…It was proposed that the significant part of a peptide could be cleared out from blood by kidneys, whereas a small fraction distributes into some compartment from which the active peptide is released slowly into the blood stream [52]. The low molecular weight compound diclofenac has exponential decrease of concentration to zero with circulating half-life of about 2 h and finally eliminates from the blood flow at 10 h [54]. The stability of sevanol in blood was most likely greater than the rate of elimination/deponation of Ugr9-1.…”

Hyaluronan-Loaded Liposomal Dexamethasone–Diclofenac Nanoparticles for Local Osteoarthritis Treatment

“…DIC is a non-steroidal compound with significant anti-rheumatic, anti-inflammatory, analgesic, and antipyretic effects that can be used to treat rheumatic or non-rheumatic inflammatory pain, and even post-operation pain control [ 32 ]. Oral administration of DIC could be rapidly absorbed but only about 50% could be metabolized and available systemically [ 33 ]. Following treatment, DIC binds extensively to plasma albumin and is attained in synovial fluid with substantial concentrations [ 33 ].…”

“…Oral administration of DIC could be rapidly absorbed but only about 50% could be metabolized and available systemically [ 33 ]. Following treatment, DIC binds extensively to plasma albumin and is attained in synovial fluid with substantial concentrations [ 33 ]. There are two major routes to metabolite diclofenac in humans: the acyl glucuronidation which could be catalyzed by uridine 5’-diphosphoglucuronosyl transferase 2B7 and phenyl hydroxylation catalyzed by cytochrome P4502C9 and 3A4 [ 34 ].…”

Inclusion Complexes of Non-Steroidal Anti-Inflammatory Drugs with Cyclodextrins: A Systematic Review

“…Hamilton et al, 2018 [39] Diclofenac/HP-β-CD Evaluated the pharmacokinetics of diclofenac and HP-β-CD in patients with mild or moderate renal insufficiency or mild hepatic impairment (clinical study).…”