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 (V z ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between V z (but not CL or elimination half‐life, t ½ ) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t ½ . 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).

Purpose: The analgesic and opioid-sparing effects of nonsteroidal anti-inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl-beta-cyclodextrin (HP beta CD)-diclofenac is an injectable formulation of diclofenac solubilized with HP beta CD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HP beta CD-diclofenac.Methods: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55-82 years old stratified into three groups and receiving HP beta CD-diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HP beta CD-diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects.Results: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age-and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t(1/2)), likely due to a decrease in the volume of distribution (V-z) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation.Conclusion: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HP beta CD-diclofenac but indicates that diclofenac CL increases with increasing body weight.

Background: Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events.Objective: This study evaluated the proarrhythmic potential of hydroxypropyl-beta-cyclodextrin (HP beta CD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-beta-cyclodextrin (HP beta CD), on ventricular electrical conduction in preclinical and clinical models.Methods: We assessed the effects of diclofenac, HP beta CD, and HP beta CD-diclofenac on the human delayed rectifier potassium channel (I-Kr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-a-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HP beta CD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin).Results: In vitro, diclofenac produced no statistically significant effect on I-Kr. Significant, non-dose-dependent effects were observed in the presence of HP beta CD or HP beta CD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HP beta CD in this in vitro model. In vivo, neither HP beta CD-diclofenac dose resulted in QTc prolongation >= 2 ms (>= 5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HP beta CD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms.Conclusions: The findings from the present study suggest that HP beta CD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538. (C) 2013 Elsevier HS Journals, Inc. All rights reserved.

Objectives:A novel injectable formulation of diclofenac, Dyloject, utilizes hydroxypropyl-&bgr;-cyclodextrin (HP&bgr;CD) as a solubilizing agent, allowing dosing as a small-volume intravenous bolus for postoperative pain. In this test of the efficacy and safety of HP&bgr;CD diclofenac, we hypothesized that HP&bgr;CD diclofenac would relieve moderate and severe pain after orthopedic surgery. Patients and Methods:Adults 18 to 85 years old with moderate and severe pain within 6 hours after surgery were randomized to HP&bgr;CD diclofenac, ketorolac tromethamine, or placebo, and stratified by risk cohort. The HP&bgr;CD diclofenac non–high-risk cohort dose was 37.5 mg, the high-risk cohort received 18.75 mg, and patients ≥95 kg received 50 mg. The ketorolac dose was 30 mg in the non–high-risk and high-weight cohorts and 15 mg in the high-risk cohort. Rescue intravenous morphine was given for pain as needed. Efficacy was measured by the sum of pain intensity differences (SPID). Results:Mean SPID scores of 277 patients were significantly better with HP&bgr;CD diclofenac and ketorolac than with placebo (P<0.0001), across all risk cohorts (P<0.05). HP&bgr;CD diclofenac was associated with better SPID scores, faster onset of analgesia, and significantly lower opioid requirement (P<0.008) than ketorolac. In patients more than or equal to 65 years, HP&bgr;CD diclofenac was associated with significantly better analgesic efficacy (P=0.05), and lower opioid requirement versus ketorolac. The incidence of treatment-related adverse events was similar across groups. Discussion:HP&bgr;CD diclofenac is safe and efficacious for acute moderate and severe pain after orthopedic surgery and significantly spares morphine use.