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

Douglas A Hamilton, Cynthia C Ernst, William G Kramer, Donna Madden, Eric Lang, Edward Liao, Peter G Lacouture, Atulkumar Ramaiya, Daniel B Carr, Douglas A Hamilton, Cynthia C Ernst, William G Kramer, Donna Madden, Eric Lang, Edward Liao, Peter G Lacouture, Atulkumar Ramaiya, Daniel B Carr

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).

Keywords: NSAID; hepatic; pharmacokinetics; renal; safety.

© 2017 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean plasma concentrations of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of intravenous HPβCD‐diclofenac in subjects with renal insufficiency or hepatic impairment. (A,B) Mean plasma diclofenac (A) and HPβCD (B) concentrations following intravenous administration of a single dose of HPβCD‐diclofenac 37.5 mg in patients with mild or moderate renal insufficiency and healthy subjects. (C,D) Mean plasma diclofenac (C) and HPβCD (D) concentrations following intravenous administration of a single dose of HPβCD‐diclofenac 37.5 mg in patients with mild hepatic impairment and healthy subjects. Data points represent mean values (values below LLOQ were considered zero; thus, some mean values are

Figure 2

Mean plasma concentrations of hydroxypropyl‐β‐cyclodextrin…

Figure 2

Mean plasma concentrations of hydroxypropyl‐β‐cyclodextrin (HPβCD) in healthy subjects following administration of intravenous…

Figure 2
Mean plasma concentrations of hydroxypropyl‐β‐cyclodextrin (HPβCD) in healthy subjects following administration of intravenous HPβCD‐diclofenac and intravenous itraconazole. intravenous HPβCD‐diclofenac 37.5 mg (333.3 mg HPβCD), and intravenous itraconazole 200 mg (8000 mg HPβCD) were both given as a single dose. Data points represent mean values (values below the LLOQ were considered zero), and error bars represent the standard deviation (SD) of the mean. The results of the comparison in healthy subjects do not include adjustments for differences in doses of HPβCD between HPβCD‐diclofenac and intravenous itraconazole.
Figure 2
Figure 2
Mean plasma concentrations of hydroxypropyl‐β‐cyclodextrin (HPβCD) in healthy subjects following administration of intravenous HPβCD‐diclofenac and intravenous itraconazole. intravenous HPβCD‐diclofenac 37.5 mg (333.3 mg HPβCD), and intravenous itraconazole 200 mg (8000 mg HPβCD) were both given as a single dose. Data points represent mean values (values below the LLOQ were considered zero), and error bars represent the standard deviation (SD) of the mean. The results of the comparison in healthy subjects do not include adjustments for differences in doses of HPβCD between HPβCD‐diclofenac and intravenous itraconazole.

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Source: PubMed

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