P-084 - (Poster #84) Comparative Systemic Bioavailability of Topical Diclofenac Sodium Gel 1% vs Topical Diclofenac Diethylamine Gel 1.16%

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) widely used to treat localized pain and inflammation in osteoarthritis (OA) of the knee and other musculoskeletal conditions.  Topical formulations aim to deliver high local tissue concentrations while minimizing systemic exposure and GI adverse effects associated with oral NSAIDs. Two commonly marketed topical salt forms are diclofenac diethylamine (DDEA) gel (Voltaren® Emulgel®, 1.16% w/w) and diclofenac sodium  gel (DSG) (1% w/w). While clinical trials have established the efficacy and safety of topical DDEA gel in over 32,000 patients, comparative data on systemic absorption between the two salts are limited. Additionally, patients often apply heat or perform mild exercise after topical NSAID application, and the effects of these co‑interventions on drug absorption have not been fully characterized. Understanding whether heat or exercise alters systemic exposure is critical to ensure consistent safety and efficacy profiles across formulations. This study therefore compared steady‑state systemic bioavailability of DSG 1% versus DDEA gel 1.16% and assessed how heat application or moderate treadmill exercise influences absorption from DSG in healthy older volunteers to inform labeling.

Purpose/Objectives:

The primary objectives of the study were to compare systemic exposure and determine relative bioavailability of diclofenac following repeated dosing of DSG 1% versus DDEA gel 1.16% and to determine the effects of heat application and of moderate exercise on the systemic absorption of DSG 1%. The secondary objective was to evaluate the general and local tolerability of DSG 1%.

Methods:

This single-center, open-label, randomized, 4-treatment, double 3-period crossover study enrolled 36 healthy adult volunteers (12 males, 24 females; aged 50-78 years).  Fourteen-day washouts were observed between 7-day treatment periods.

All subjects received DSG without co-intervention (A) and DDEA (B), and were randomized 1:1 to receive DSG+heat (C) or DSG+exercise (D) in two three-way crossover arms:  Arm 1 compared treatments A, B and C; Arm 2 compared treatments A, B and D.  Each period, subjects applied 4 g gel to one knee (≈400 cm2) four times daily.  For treatment C, a standard heating pad (moderate heat) was applied for 15 minutes before each dose.  For treatment D, subjects walked on a treadmill for 20 minutes under supervision, 10 minutes after morning dose.

Blood samples were collected predose on Days1-7, then every 2h after dosing through 24h on Day7.  Urine was collected on Day 1 and all fractions on Day7.  Plasma/urine assays used validated LC-MS/MS (LOQ: 0.5 ng/mL plasma, 3 ng/mL urine).  C_max, AUC_0-24 and C_min were derived by non-compartmental analysis.  Bioavailability was compared (B, C and D vs A) with crossover ANOVA on log-transformed C_max and AUC with 90% CIs.  Safety was monitored by recording adverse-events, vital signs and physical examination.

 

Results:

Of 36 randomized subjects, 34 completed all study periods (two discontinued: one for incorrect treatment application, one for acute allergic contact dermatitis of the knee).  The PK population was evenly distributed between Arm 1 and Arm 2 for comparison. 

DDEA gel vs DSG (B vs A):  Systemic exposure from DDEA gel was marginally lower than DSG.  Mean AUC_0-24 was 194±95.9 ng•h/mL (DDEA gel) vs. 222±140 ng•h/mL (DSG); the geometric mean ratio (GMR) was 90.7% with 90% confidence interval (CI) 82.7-99.5%, which is within the bioequivalence range.  Mean C_max were 14.0±8.9 ng/mL (DDEA gel) vs. 22.2±33.3 ng/mL (DSG) with GMR 85.3% (90% CI: 69.3-105).

DSG with heat vs DSG (C vs A):  Systemic exposure from DSG with heat was lower than DSG without heat.  Mean AUC_0-24 was 179±63.2 ng•h/mL (with heat) vs 218 ± 148ng•h/mL (without heat); the GMR was 92.5% (90% CI: 77.3-111).  This reduction is not considered clinically meaningful.  Mean C_maxwere 13.3±5.6 ng/mL (with heat) vs 24.5±42.0 ng/mL (without heat) with GMR 90.0% (90% CI: 61.9-131).  Despite this decline, urinary diclofenac excretion remained unchanged, indicating equivalence between treatments.

DSG with moderate exercise (ME) vs without ME (D vs A):  Systemic exposure from DSG with ME ws marginally higher than DSG Without ME.  Mean AUC_0-24 were 234±134 ng•h/mL (with ME) vs 226±135 ng•h/mL (without ME) with GMR 103% (90% CI: 87.8-120). which is within the bioequivalence range.  Mean C_max were 16.8±10.1 ng/mL (with ME) vs 19.8±21.5 ng/mL (without ME) with GMR 99.2% (90% CI: 74.6-132).

Urinary excretion of diclofenac was consistently low (approximately o.5% of applied dose) and similar for all study regimens.

Trough diclofenac plasma levels seemed to plateau from Day1 through Day6 but then resumed an upward trend over Days7 and 8 indicating conditions that were at or near steady-state.

No serious adverse events (AEs) occurred during the study.  There was low incidence of suspected-related events (mainly mild local reactions) that was similar for DSG without exercise (18 and 19%, respectively). Incidence of suspected-related events was lower for DDEA gel (8%) and no related AE occurred after application of DSG with heat.

Conclusions/Implications for future research and/or clinical care:

Topical DSG 1% and topical DDEA gel 1.16% yield similar systemic diclofenac exposure at or near steady-state conditions, indicating similar pharmacokinetic profile in systemic absorption. No clinically relevant difference in systemic exposure was observed when heat or exercise was applied concomitant with DSG. All treatments were well-tolerated. These findings strongly suggest that DSG 1% is comparable to Diclofenac DEA gel 1.16%.  Furthermore, patients can engage in moderate exercise or apply heat near the application site without compromising systemic safety. Overall, this work supports flexible, patient‑friendly use of either topical diclofenac formulation without special activity restrictions.