The Journal of Clinical Pharmacology

http://www.jclinpharm.org Systemic Bioavailability of Topical Diclofenac Sodium Gel 1% Versus Oral Diclofenac Sodium in Healthy Volunteers
Jean-Luc Kienzler, Morris Gold and Fabrice Nollevaux J. Clin. Pharmacol. 2010; 50; 50 originally published online Oct 19, 2009; DOI: 10.1177/0091270009336234 The online version of this article can be found at: http://www.jclinpharm.org/cgi/content/abstract/50/1/50

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Pharmacokinetics title

Systemic Bioavailability of Topical Diclofenac Sodium Gel 1% Versus Oral Diclofenac Sodium in Healthy Volunteers
Jean-Luc Kienzler, MD, ACCA, FFPM, Morris Gold, ScD, and Fabrice Nollevaux, MSc

Systemic bioavailability and pharmacodynamics of topical diclofenac sodium gel 1% were compared with those of oral diclofenac sodium 50-mg tablets. In a randomized, 3-way crossover study, healthy volunteers (n = 40) received three 7-day diclofenac regimens: (A) 16 g gel applied as 4 g to 1 knee 4 times daily (4 g on surface area 400 cm2), (B) 48 g gel applied as 4 g per knee 4 times daily to 2 knees plus 2 g gel per hand applied 4 times daily to 2 hands (12 g on 1200 cm2), and (C) 150 mg oral diclofenac applied as 50-mg tablets 3 times daily. Thirty-nine participants completed all 3 regimens. Systemic exposure was greater with oral diclofenac (AUC0-24, 3890 1710 ngh/mL) than with topical treatments A (AUC0-24, 233 128 ngh/mL) and B (AUC0-24, 807 478 ngh/mL). Oral diclofenac inhibited platelet aggregation,

cyclooxygenase-1 (COX-1), and COX-2. Topical diclofenac did not inhibit platelet aggregation and inhibited COX-1 and COX-2 less than oral diclofenac. Treatment-related adverse events were mild and limited to application site reactions with diclofenac sodium gel 1% (n = 4) and gastrointestinal reactions with oral diclofenac (n = 3). Systemic exposure with diclofenac sodium gel 1% was 5- to 17-fold lower than with oral diclofenac. Systemic effects with topical diclofenac were less pronounced. Keywords: Diclofenac; absorption; bioavailability; pharmacokinetics; pharmacodynamics Journal of Clinical Pharmacology, 2010;50:50-61 2010 the American College of Clinical Pharmacology

onsteroidal anti-inflammatory drugs (NSAIDs) are a preferred therapy for osteoarthritis (OA) because they effectively relieve pain and reduce inflammation with generally good tolerability.1-5 The pain relief and anti-inflammatory activity provided by NSAIDs are associated primarily with inhibition of cyclooxygenase-2 (COX-2).6 COX-2 is induced during inflammation by cells, such as synoviocytes in the joint capsule, and at other times is present at low levels. COX-1 is constitutively expressed throughout the body under normal conditions. The gastrointestinal toxicity, platelet inhibition, and other adverse events (AEs) seen with the oral NSAID class are
From Novartis Consumer Health SA, Nyon, Switzerland (Dr Kienzler); Novartis Consumer Health, Parsippany, New Jersey (Dr Gold); and SGS Life Science Services, Wavre, Belgium (Mr Nollevaux). Submitted for publication November 26, 2008; revised version accepted March 29, 2009. Address for correspondence: Jean-Luc Kienzler, MD, ACCA, FFPM, Head of Clinical Pharmacology, Novartis Consumer Health SA, Route de lEtraz 2, PO Box 1279, CH-1260 Nyon 1, Switzerland; e-mail: jean-luc.kienzler@novartis .com. DOI: 10.1177/0091270009336234

associated primarily with the inhibition of COX-1.7 There is evidence that risk of AEs increases with increasing dose and duration of systemic exposure to NSAIDs and COX-2 inhibitors.8-12 Topical NSAIDs represent a potential alternative to oral NSAIDs, offering a similar mechanism of action following local administration with less systemic exposure.13,14 The NSAID diclofenac has been available in oral formulation since 1983 and topical formulation as a diethylamine salt (1.16% diclofenac diethylamine Emulgel equivalent to 1% diclofenac sodium gel) since 1985 (outside the United States). The pharmacology, clinical efficacy, and safety of oral and topical diclofenac formulations have been studied extensively.15,16 In a pharmacokinetic study, participants treated over a large skin surface with diclofenac sodium 0.1% gel had 1% to 3% of the systemic exposure to diclofenac compared with the recommended 75-mg over-the-counter daily dose of oral diclofenac sodium.17 In active-comparator trials, topical diclofenac gel or solution was as effective as oral diclofenac or ibuprofen in patients with OA of the hand or knee but with fewer systemic AEs.18,19

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DICLOFENAC PHARMACOKINETICS Diclofenac sodium gel 1% is a new topical formulation, pharmacologically similar to 1.16% diclofenac diethylamine gel. Diclofenac sodium gel 1% was approved with a maximum daily dose of 32 g by the US Food and Drug Administration (FDA) in October 2007 for the relief of pain of OA of joints amenable to topical treatment, such as the knees and those of the hands, making it the first topical NSAID approved in the United States.20 The current study was designed to compare the systemic bioavailability of (A) 4 g diclofenac sodium gel 1% applied topically 4 times daily to 1 knee or (B) 12 g applied 4 times daily to both knees and hands versus (C) diclofenac sodium 50-mg enteric-coated tablets taken orally 3 times daily. METHODS Study Design This 7-week, single-center, randomized, open-label, multiple-dose, 3-way crossover study compared the systemic bioavailability of diclofenac sodium gel 1% with oral diclofenac in healthy participants. The protocol for the study was approved by the Institutional Review Board (IRB) of the clinical center that conducted the study (Commissie voor Medische Ethiek, ZNA/OCMW Antwerpen, Antwerp, Belgium) and was conducted in accordance with the Declaration of Helsinki, European Directive 91/507/EEC, and US 21 Code of Federal Regulations dealing with clinical studies, parts 50 and 56, concerning Informed Patient Consent and IRB approval. All participants provided informed consent before participating. Participants Participants included healthy volunteers aged 50 years. To approximate the general OA population, it was decided in advance that at least half of all participants would be aged 60 years and that 50% to 70% would be women. Health status was confirmed by standard physical examination and vital signs and by laboratory workup, including the assessment of blood hematology and blood chemistry. Participants were excluded from the study if they had been previously treated with diclofenac within 2 weeks of the start of the study; if they required treatment with any topical or systemic medication during the study period, excluding hormone replacement therapy or contraceptives; or if they were pregnant or had any active clinically relevant disorder that might compromise patient welfare or confound the study results. Interventions The investigational therapy was topical diclofenac sodium gel 1%, and the reference therapy was diclofenac sodium enteric-coated 50-mg tablets. Participants underwent health status screening within 21 days before the start of the study, after which they were randomly assigned in equal numbers to 1 of 6 possible treatment sequences, each consisting of three 7-day drug treatment periods separated by 14-day washout periods (Figure 1). Men and women were randomized separately to ensure an equal distribution of treatment sequences within each sex. The treatment regimens were designated as treatment A, B, or C. For treatment A, participants applied 4 g of diclofenac sodium gel 1% to 1 knee, designated as the target knee, 4 times daily for 7 days, at approximately 7:00, 12:00, 17:00, and 22:00 hours. With this schedule, a total daily dose of 16 g gel (160 mg diclofenac) was applied to approximately 400 cm2 of skin. For treatment B, participants applied 4 g to each knee and 2 g to each hand 4 times daily for 7 days, at approximately 7:00, 12:00, 17:00, and 22:00 hours. Because the application area was approximately 400 cm2 on each knee and approximately 200 cm2 on each hand, the total daily dose for treatment B was 48 g of gel (480 mg diclofenac) applied to approximately 800 cm2 of skin on the knees and approximately 400 cm2 of skin on the hand or approximately 1200 cm2 of skin in total. Thus, although treatments A and B were each applied at the rate of 1 g gel per 25 cm2 of skin, treatment B was applied to 3 times the area of skin. The maximum daily dose of 48 g gel used in this study (treatment B) was higher than the FDAapproved maximum daily dose of 32 g gel. For treatment C, oral diclofenac 50 mg was administered 3 times daily for 7 days at about 7:00, 13:00, and 19:00 hours, before meals with about 240 mL of water. This represents a total daily dose of 150 mg diclofenac. A dosing card was supplied for treatments A and B to standardize dosing. The study gel was applied to the front of the knee, with specific attention to the medial and lateral area, with light massage for no more than 1 minute until the gel had vanished. Similar methodology was used as the study gel was evenly applied to each hand. From day 1 to day 6, the first dose was supervised in the clinical center, and the 3 remaining doses were applied by the participants at home. On day 7, all doses were supervised at the clinical center.

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KIENZLER ET AL

The following pharmacokinetic parameters were calculated for each participant:

Day 1, treatment Bthe area under the plasma concentration versus time curve from 0 to 24 hours (AUC0-24) Day 1, treatments A and Btotal urinary excretion over 24 hours (Ae0-24) of unchanged diclofenac and 4-OH-diclofenac Day 7, all treatmentsminimum concentration (Cmin); maximum concentration (Cmax); time to Cmax (tmax); AUC0-24; average plasma concentration (Cav; ie, AUC0-24/24); peak-trough fluctuation (ie, Cmax-Cmin/Cav); and Ae0-24 of diclofenac and 4-OH-diclofenac

Figure 1. Study design.

Storage conditions for each study drug were described on the label. Medications were administered open label; however, the analytical laboratory remained blinded to the treatment sequence during the analysis of the plasma samples. Assessments Lithium heparinized blood samples were collected for pharmacokinetic assessments at scheduled time points from day 1 through day 7 in each dosing period. On day 1, urine was sampled immediately before the morning dose for all treatments and was collected for 24 hours after the morning dose for treatments A and B. On day 7, urine was collected for 24 hours after the morning dose for all treatments. The pharmacokinetic sampling plan is summarized in Table I. Plasma assays of diclofenac sodium and urinary assays of diclofenac and its hydroxylated metabolite (4-OH-diclofenac) were performed according to good laboratory practice guidelines, using a fully validated liquid chromatography coupled to tandem mass spectrometry method with lower limits of quantification of 0.5 ng/mL (plasma) and 3 ng/mL (urine). 52 J Clin Pharmacol 2010;50:50-61

All pharmacokinetic parameters were calculated without interpolation. AUC0-24 was calculated using the linear trapezoidal rule. Participants treated with topical diclofenac sodium gel 1% during period 3 (treatments A or B) were followed for 35 days beyond the 7 days of dosing (days 50-84 relative to the first dose of the first period, days 8-42 relative to the first dose of period 3) to track the persistence of diclofenac in the systemic circulation. This was quantified as the proportion of participants with measurable diclofenac levels at study days 70 1, 77 1, and 84 1. Pharmacodynamic outcome measures included inhibition of COX-1, COX-2, and platelet aggregation. COX-1 and COX-2 were indirectly assessed by measuring plasma thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) levels at the screening visit and on day 7 before and 2 hours after the morning dose. Aliquots for both TXB2 and PGE2 were stored at 80C until shipment on dry ice to the laboratory. All samples were still frozen on receipt and were stored below 65C until they were assayed using a commercial enzyme immunoassay kit (Cayman Chemical, Ann Arbor, Michigan). Inhibition of platelet aggregation was assessed from blood samples taken at the screening visit and 2 hours after the first dose of day 7. Aliquots collected in 3.8% sodium citrate at a final dilution of 1:10 were sent to the Center for Molecular and Vascular Biology (Leuven, Belgium) for analysis using the photo-optical/turbidimetric method.21,22 Safety was assessed as incidence rates of treatmentemergent AEs (coded according to the Medical Dictionary for Regulatory Activities [MedDRA], Version 7.1), further summarized within body systems. Each AE was attributed to the treatment administered most recently before the onset of the AE. For each unique MedDRA AE code, incidence rates were subdivided further with respect to maximum severity and relationship to study drug. Other safety assessments included changes in physical findings and vital signs.

DICLOFENAC PHARMACOKINETICS Table I Blood Samples Taken for Pharmacokinetic Purposes

Treatment Code Lithium-Heparinized Blood Samples

Immediately before the first dose on days 1, 2, and 5 to 7; every 2 hours after the first dose through 24 hours (except for 22 hours) on day 7; in the morning of study days 70 1, 77 1, and 84 1 when treatment A was given in period 3. Immediately before the first dose on days 1 and 5 to 7; every 2 hours after the first dose through 24 hours (except for 22 hours) on days 1 and 7 and in the morning of study days 70 1, 77 1, and 84 1 when treatment B was given in period 3. Immediately before the first dose on days 1, 2, and 5 to 7 and at the following time points (h) after the first dose on day 7: 0.5, 1.0, 1.33, 1.67, 2.0, 2.33, 2.67, 3.0, 3.5, 4.0, 5.0, 6.0 (before second administration), 6.5, 7.0, 7.33, 7.67, 8.0, 8.33, 8.67, 9.0, 9.5, 10.0, 11.0, 12.0 (before third administration), 12.5, 13.0, 13.33, 13.67, 14.0, 14.33, 14.67, 15.0, 15.5, 16.0, 17.0, 18.0, 20.0, and 24.0.
Treatment A = diclofenac sodium topical gel 1% on 1 knee; treatment B = diclofenac sodium topical gel 1% on 2 knees and 2 hands; treatment C = diclofenac sodium 50-mg tablets.

Inhibition of each pharmacodynamic parameter was computed as change from screening to a later time point divided by the value at screening. There was 1 such ratio for platelet aggregation (day 7 vs screening) and 2 ratios for TXB2 and PGE2 (1 for day 7 before the morning dose vs screening and 1 for day 7 at 2 hours after the morning dose vs screening). Each inhibition value for platelet aggregation and TXB2 was analyzed in a mixed effects ANOVA model that included treatment sequence, subject within sequence, treatment, and period as effects and the screening value (denominator of the inhibition ratio) as a covariate. Because of excessive departure from normality, the median value was used to summarize inhibition of PGE2, and differences between treatments in inhibition of PGE2 were tested with the nonparametric Wilcoxon signed rank test. RESULTS Participants Of 94 participants screened, 18 were deemed ineligible because they met exclusion criteria, withdrew consent, or failed to show up at the start of the study. Of the remaining 76 eligible participants, the first 40 were randomized, with 6 or 7 participants assigned to each of the 6 possible treatment sequences. The demographic characteristics of the 40 enrolled participants are summarized in Table II. Thirty-nine participants (98%) completed the study. One participant on sequence C-A-B discontinued for personal reasons after the morning tablet intake on day 6 of period 1 (treatment C). Of 25 participants who received treatment A or B during period 3, 22 (88%) agreed to participate in the follow-up part of the study. All 39 participants who completed the study were fully compliant with dosing over all 7 days of each period. The participant who withdrew was fully compliant with oral dosing of treatment C for 5 days in period 1. Thus, treatment C was administered to 40 participants, whereas treatments A and B were each administered to 39 participants. Absorption and Plasma Pharmacokinetics Detectable plasma levels of diclofenac were found after the 2-week washout period in 38% (10 of 26) of patients following treatment A (maximum level detected 2.8 ng/mL), in 63% (17 of 27) of patients following treatment B (maximum level detected 1.9 53

Statistical Analysis Continuous pharmacokinetic parameters on day 7 were analyzed in the logarithmic (log) scale with analysis of variance (ANOVA), including effects of sequence, subject within sequence, period, and treatment. Differences of least squares (LS) means (between treatments B and A, A and C, and B and C) and associated 90% confidence intervals (CIs) in the log scale were exponentiated to yield estimated ratios of pharmacokinetic parameters (B/A, A/C, and B/C) in the original scale and associated 90% CIs. Drug accumulation from day 1 to day 7 was assessed by analyzing AUC0-24 (treatment B only) in the log scale with an ANOVA that included subject and day as effects. The day 7 versus day 1 ratio for AUC0-24 and 90% CI was then computed by exponentiating from the log scale, as described above. This procedure was also applied to log-transformed day 1 and day 7 values of Ae0-24 for diclofenac and for 4-OH-diclofenac separately for treatments A and B.
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KIENZLER ET AL ng/mL), and in 23% (6 of 26) of patients following treatment C (maximum level detected 6.8 ng/mL). These levels were considered minimal and unlikely to bias pharmacokinetic parameters estimated on day 7 of the next period, at which point the participants would have completed a week of dosing with the subsequent treatment. However, there were 7 participants who had a measurable day 1 predose diclofenac plasma level in the period in which treatment B was given, and plasma was sampled throughout day 1. For these participants, day 1 AUC0-24 might show a slight upward bias. Treatments A and B were each applied at the rate of 1 g gel per 25 cm2 of skin, but treatment B was applied to approximately 3 times the skin surface relative to treatment A. Corresponding to this difference in application site area, diclofenac plasma concentrations on day 7 for treatment B were approximately 3-fold higher than those for treatment A. For treatment A, mean day 7 diclofenac concentrations at each time point over the 24-hour period were between 8 and 12 ng/mL (SD 5-7 ng/mL). For treatment B, mean day 7 diclofenac concentrations at each time point were 30 to 40 ng/mL (SD 20-30 ng/mL). There were no obvious peaks in absorption related to topical diclofenac sodium gel 1% application. For treatment C, mean day 7 diclofenac concentrations ranged from 17 ng/mL (SD 12 ng/mL) to 796 ng/mL (SD 1031 ng/mL). There were clear peak plasma concentrations approximately 1 hour after each administration. The average plasma profiles for both topical diclofenac sodium gel 1% regimens and oral diclofenac tablets are shown in Figure 2. Pharmacokinetic parameters derived from the plasma concentrations on day 7 are summarized in Table III. Median tmax for treatments A (14 hours) and B (10 hours) centered around 12 hours following the 7:00 dose. Given minimal variation in diclofenac concentrations from time point to time point with the topical treatments, tmax would naturally center on the midpoint of the 24-hour assay period. Median tmax for treatment C was 6.5 hours after the morning dose. As plasma diclofenac levels spiked after each dose, the dose associated with tmax varied randomly from participant to participant. Consequently, the distribution of tmax centered on the period immediately following the middle dose. The AUC0-24 and Cav for treatment C were 17-fold higher than for treatment A and 5-fold higher than for treatment B. Cmax for treatment C was approximately 150-fold higher than for treatment A and 40-fold higher than for treatment B. The peak-trough fluctuation was approximately 100% for both topical treatments and approximately 1500% for the 54 J Clin Pharmacol 2010;50:50-61 Table II Demographic Characteristics of the Study Population
All Participants (N = 40)

Men, % White, % Mean (SD) Range Mean (SD) Range Mean (SD) Range Mean (SD) Range

age, y weight, kg height, cm BMI, kg/m2

50.0 100 59.9 (5.7) 50-74 74.2 (12.3) 52-103 169.7 (9.3) 147-187 25.6 (2.7) 20.4-33.0

BMI, body mass index.

oral treatment. The greater differences in Cmax and peak-trough fluctuation seen with treatment C compared with A or B are consistent with the clear postdose peaks that were seen after oral administration but not after topical administration. Least squares geometric mean ratios between the treatments for exposure to diclofenac based on Cmax and AUC0-24 are shown in Table IV. Systemic exposure on day 7 was 3 to 4 times higher from treatment B than from treatment A (Cmax, 349% [90% CI, 302%-403%]; AUC0-24, 340% [90% CI, 294%-394%]). Following administration of 4 g diclofenac sodium gel 1% to 1 knee, the LS mean ratio for AUC0-24 was approximately 6% relative to oral therapy. Following administration of 12 g diclofenac sodium gel 1% to both knees and hands, the LS mean ratio for AUC0-24 was approximately 20% compared with oral therapy. The LS mean ratios for Cmax following diclofenac sodium gel 1% application to 1 knee and diclofenac sodium gel 1% application to both knees and hands were 0.6% and 2.2%, respectively, compared with oral diclofenac. From day 1 to day 7, diclofenac from topical treatment B accumulated to a moderate extent in plasma. The first mean plasma level of diclofenac above the lower limit of quantification occurred 2 hours following the first dose on day 1, after which the mean level increased in a steady, linear fashion to a peak of 15 ng/mL after 24 hours (day 2 predose). In contrast, the mean day 7 predose value in treatment B was 35 ng/ mL. The mean AUC0-24 for treatment B increased from 188 86.4 ngh/mL on day 1 to 807 478 ngh/mL on day 7. From the logarithmic analysis of AUC0-24, the estimated ratio of accumulation from day 1 to day 7 was 417% (90% CI, 367%-474%; Table IV). The follow-up plasma samples after period 3 collected 21, 28, and 35 days posttreatment

DICLOFENAC PHARMACOKINETICS Table III

Treatment Cmax, ng/mL

Summary of Day 7 Plasma Pharmacokinetic Parameters

tmax, h AUC0-24, ngh/mL Cmin, ng/mL Cav, ng/mL PTF, %

A (n = 39) B (n = 39) C (n = 39)

15.0 7.33 53.8 32.0 2270 778

14 (0-24) 10 (0-24) 6.5 (1-14)

233 128 807 478 3890 1710

5.92 3.65 19.2 12.1 5.70 3.11

9.70 5.32 33.6 19.9 162 71.2

95.6 40.4 106 51.6 1516 615

All data are mean SD, except median (range) for tmax. AUC0-24, area under the plasma concentration versus time curve from 0 to 24 hours; Cav, average plasma concentration; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; PTF, peak-trough fluctuation; tmax, time to Cmax. Treatment A = diclofenac sodium topical gel 1% on 1 knee; treatment B = diclofenac sodium topical gel 1% on 2 knees and 2 hands; treatment C = diclofenac sodium 50-mg tablets.

Figure 2. Day 7 plasma absorption of diclofenac from topical versus oral administration. Oral = treatment C (3 50 mg/d); topical maximum exposure = treatment B (4 12 g/d applied on 2 knees and 2 hands); topical typical exposure = treatment A (4 4 g/d applied on 1 knee).

showed that diclofenac concentrations generally dropped to undetectable levels over the weeks following the end of topical diclofenac sodium gel 1% administration. Of 11 participants who received treatment A in period 3, none had measurable plasma diclofenac levels 28 days posttreatment versus 3 (27%) of 11 participants who received treatment B during period 3. Maximum concentration for these 3 participants was 2.6 ng/ mL. On day 35 posttreatment, only 1 of the 3 participants had a measurable diclofenac concentration (0.8 ng/mL).

Excretion and Urine Pharmacokinetics Table V summarizes urinary excretion of diclofenac and its hydroxylated metabolite, 4-OH-diclofenac, for treatments A and B on day 1 and for all 3 treatments on day 7. LS geometric mean ratios of Ae0-24 between the treatments are shown in Table IV. Urinary excretion on day 7 was 2 to 3 times higher during treatment B than during treatment A (diclofenac, 273% [90% CI, 224%-332%]; 4-OH-diclofenac, 250% [90% CI, 207%-302%]). This is similar to corresponding results for AUC0-24 in plasma, also

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KIENZLER ET AL Table IV Ratios (%) of Primary Pharmacokinetic Parameters Between Treatments for Day 7 and Between Day 7 and Day 1 for Treatments A and B
Comparison (n = 39) Cmax AUC0-24 Ae0-24 Diclofenac Ae0-24 4-OH-Diclofenac

Day 7 ratio, % Treatment B/treatment A Treatment A/treatment C Treatment B/treatment C Day 7/day 1 ratio, % Treatment A Treatment B

349 (302-403) 0.63 (0.548-0.733) 2.21 (1.91-2.56)

340 (294-394) 5.79 (5.00-6.70) 19.70 (17.0-22.8) 417 (367-474)

273 (224-332) 2.51 (2.06-3.06) 6.85 (5.63-8.34) 493 (417-581) 285 (248-327)

250 (207-302) 2.21 (1.82-2.68)a 5.52 (4.56-6.69)a 666 (561-790) 402 (350-462)

Estimate of ratio (%) of least squares geometric means (90% confidence interval) derived from analysis of variance. Ae0-24, total urinary excretion over 24 hours; AUC0-24, area under the plasma concentration versus time curve from 0 to 24 hours; Cmax, maximum plasma concentration. Treatment A = diclofenac sodium topical gel 1% on 1 knee; treatment B = diclofenac sodium topical gel 1% on 2 knees and 2 hands; treatment C = diclofenac sodium 50-mg tablets. a. n = 38.

Table V Summary of Urine Pharmacokinetic Parameters, Days 1 and 7

Ae0-24 Diclofenac, g Treatment Day 1 Day 7 Day 1 Ae0-24 4-OH-Diclofenac, g Day 7

A (n = 39) B (n = 39) C (n = 39)

64.1 64.1 249 118

265 164 672 300 10 300 3980

95.0 85.5 333 160

539 332 1270 602 23 400 6280a

Values presented as mean SD. Ae0-24, total urinary excretion over 24 hours. Treatment A = diclofenac sodium topical gel 1% on 1 knee; treatment B = diclofenac sodium topical gel 1% on 2 knees and 2 hands; treatment C = diclofenac sodium 50-mg tablets. a. n = 38.

shown in Table IV. Mean ratios of Ae0-24 for treatments A and B versus treatment C were consistent with the corresponding ratios for AUC0-24 and Cmax, indicating profoundly less systemic exposure to diclofenac from topical administration relative to oral administration. Accumulation as measured by the day 7 to day 1 ratio of mean Ae0-24 is shown in Table IV. There was more accumulation on treatment A (493% for diclofenac and 666% for 4-OH-diclofenac) than on treatment B (285% and 402%, respectively). However, these ratios, which indicated accumulation by a factor of 3 to 7, are roughly consistent with the corresponding ratio for AUC0-24 in plasma (417% for treatment B), which indicated accumulation by a factor of 4. Pharmacodynamics Pharmacodynamic parameters are summarized in Table VI, and P values for the comparisons between treatments are shown in Table VII. Platelet aggregation was minimally affected by either topical treatment. Oral diclofenac inhibited platelet aggregation to 56 J Clin Pharmacol 2010;50:50-61

a significantly greater extent compared with either topical diclofenac sodium gel 1% treatment, whether induced by arachidonic acid (P < .001) or adenosine diphosphate (P .003). Standard deviations were relatively large for both the topical and oral diclofenac treatment groups. Inhibition of TXB2 was used as a surrogate for inhibition of the COX-1 enzyme. Before the first dose on day 7, treatment A inhibited COX-1 only modestly (18%), whereas significantly greater inhibition relative to screening was seen with both treatments B (35%, P = .012) and C (37%, P = .005). Two hours after the first dose on day 7, COX-1 inhibition relative to screening decreased on treatments A and B. In contrast, COX-1 inhibition increased to 76.4% on treatment C, presumably reflecting sharply increasing postdose plasma levels of diclofenac over the first 2 hours after the first dose of day 7. The standard deviations of mean TXB2 percent inhibition values (both predose and postdose) were relatively large. Differences in COX-1 inhibition were statistically significant between the 2 topical treatments (P = .014) and between the topical and oral treatments (P < .001). Inhibition of PGE2 was used as a surrogate for inhibition of the COX-2 enzyme. Median COX-2 inhibition

DICLOFENAC PHARMACOKINETICS Table VI Summary of Percentage Inhibition of Pharmacodynamic Parameters, Day 7 (vs Screening)
Platelet Aggregation (Arachidonic Acid) Treatment 2 Hours Postdose Platelet Aggregation (ADP 5 M) 2 Hours Postdose

TXB2 (COX-1) Predose 2 Hours Postdose

c

PGE2 (COX-2) Predose 2 Hours Postdose

A (n = 39) B (n = 39) C (n = 39)

8.9 21.9 11.1 45.4c 63.4 46.5c

a

0.3 19.6 3.0 20.4d 13.5 20.4d

b

17.9 63.4 35.1 36.1c 37.3 34.0c

8.16 73.8 30.9 32.4c 76.4 20.0c

c

58.6 (393; 100) 90.7 (184; 100) 99.8 (64.6; 100)

55.5 (724; 100) 89.8 (25.0; 100) 100 (75.8; 100)

Mean percent inhibition SD except median (range) for PGE2. ADP, adenosine diphosphate; COX, cyclooxygenase; PGE2, prostaglandin E2; TXB2, thromboxane B2. Treatment A = diclofenac sodium topical gel 1% on 1 knee; treatment B = diclofenac sodium topical gel 1% on 2 knees and 2 hands; treatment C = diclofenac sodium 50-mg tablets. a. n = 37. b. n = 30. c. n = 38. d. n = 31.

Table VII

Comparisons of Percentage Inhibition of Pharmacodynamics Parameters (vs Screening) Between Treatments

P Value

Pharmacodynamic Parameter

Time Point

B vs A

A vs C

B vs C

Platelet aggregation (arachidonic acid) Platelet aggregation (ADP 5 M) TXB2 (COX-1) PGE2 (COX-2)

Day Day Day Day Day Day

7 7 7, 7, 7, 7,

predose 2 hours postdose predose 2 hours postdose

.79 .29 .012 .014 <.001 <.001

<.001 .003 .005 <.001 <.001 <.001

<.001 <.001 .76 <.001 <.001 <.001

Between-treatment P values generated by analysis of variance for platelet aggregation and TXB2 and by Wilcoxon signed rank test for PGE2. ADP, adenosine diphosphate; COX, cyclooxygenase; PGE2, prostaglandin E2; TXB2, thromboxane B2. Treatment A = diclofenac sodium topical gel 1% on 1 knee; treatment B = diclofenac sodium topical gel 1% on 2 knees and 2 hands; treatment C = diclofenac sodium 50-mg tablets.

on day 7 relative to screening was approximately 55% to 60% after treatment A, 90% after treatment B, and almost 100% after treatment C, with large ranges in predose and postdose PGE2 percent inhibition values observed. Predose levels of COX-2 inhibition on day 7 were similar to 2-hour postdose levels for all 3 treatments. COX-2 inhibition was significantly greater on treatment C than on treatment A or B (P < .001) and significantly greater on treatment B than on treatment A (P .001). Thus, oral diclofenac inhibited platelet aggregation and COX-2 to a significantly greater extent than either topical diclofenac sodium gel 1% treatment (A or B). Oral diclofenac also inhibited COX-1 to a significantly greater extent than either topical treatment regimen 2 hours after administration. Diclofenac sodium gel 1% 12 g applied to both knees and hands 4 times daily inhibited both COX-1 and COX-2 to a significantly greater extent than did diclofenac

sodium gel 1% 4 g applied to 1 knee 4 times daily. The 2 topical diclofenac sodium gel 1% regimens did not differ significantly with respect to platelet aggregation. Safety Twenty-nine of 40 participants (73%) in the safety population reported 1 AE with rates varying from 30% of participants on treatment C to 46% on treatment B. The most common category of AEs was gastrointestinal, with rates of 3% and 10% on treatments A and B, respectively, and 25% on treatment C. Only 7 participants (18%) experienced an AE considered to be potentially related to treatment. The incidence of potentially drug-related AEs (5%-8%) was similar across treatments; however, the nature of the AEs differed between topical diclofenac sodium gel 1% and oral diclofenac. Potentially treatment-related AEs

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KIENZLER ET AL after topical therapy (reported by 4 participants) were limited to local reactions, including dermatitis, erythema, pruritus, and paresthesia in both knees. In contrast, the 3 participants who reported a potentially treatment-related AE after oral administration all experienced gastrointestinal disorders, including abdominal pain, dyspepsia, and eructation. There were no deaths or serious AEs during the study, and no participant discontinued any treatment owing to an AE. There were also no clinically relevant changes in vital signs, and no emergent abnormalities were revealed during physical examination. DISCUSSION In this study, systemic exposure from a daily oral dose of 150 mg diclofenac, as measured by AUC0-24, was more than 5-fold greater than from diclofenac sodium gel 1% applied topically to both knees and hands (daily dose of 48 g of diclofenac sodium gel 1%; ie, 480 mg diclofenac) and 17-fold greater than from diclofenac sodium gel 1% applied to 1 knee (daily dose of 16 g of sodium gel 1%; ie, 160 mg diclofenac). The 48-g daily dose topical treatment (2 knees and 2 hands) was specially requested by the FDA to assess the maximum systemic exposure to diclofenac after topical applications, to better evaluate its safety. The FDA-approved maximum daily dose is lower, ie, 32 g, based on the long-term safety data provided for this dose for up to 12 months.23 The pharmacokinetics of diclofenac sodium gel 1% were proportional to the skin surface area treated (daily dose of 1 g diclofenac sodium gel 1% per 25-cm2 skin surface), so that systemic exposure from treating both knees and both hands (48 g diclofenac sodium gel 1% applied daily to 1200 cm2) was 3- to 4-fold greater than from treating 1 knee (16 g diclofenac sodium gel 1% applied daily to 400 cm2). Whereas diclofenac levels spiked after oral administration, diclofenac levels from diclofenac sodium gel 1% remained relatively constant throughout the day. Constant plasma levels following diclofenac sodium gel 1% treatment suggest that topically administered diclofenac accumulates in the skin and/or underlying periarticular and articular tissues, from which it is slowly released into the systemic circulation. This would also explain the observation that measurable levels of diclofenac in plasma were found in 38% of participants treated with diclofenac sodium gel 1% applied to 1 knee and 63% of those treated with diclofenac sodium gel 1% applied to both knees and hands, even after completion of a 14-day washout period. Follow-up of 22 participants treated with diclofenac sodium gel 1% in period 3 revealed a steady decline in diclofenac plasma levels, with essentially complete clearance in all participants within 28 days after the end of treatment. Results of this study are consistent with those from previous studies of topical diclofenac and other NSAIDs.24,25 In an 8-day study of diclofenac gel in healthy volunteers, twice-daily administration resulted in low but steady plasma concentrations throughout a 24-hour period. Although only 1 dose was administered on day 8, plasma levels in most patients increased between hours 12 and 24, suggesting that topical diclofenac was released slowly from the application site into underlying tissues before its eventual elimination.24 In another study, ketoprofen concentrations in plasma, synovial fluid, and intra-articular tissue were compared after administration of a single 30-mg ketoprofen plaster, multiple plaster applications over a 5-day period, or a single oral 50-mg tablet in 100 patients undergoing knee arthroscopy. Ketoprofen concentrations in the meniscus and cartilage were 2- to 3-fold higher than those in plasma, and median concentrations in these intra-articular tissues following topical treatment were actually 4.1- to 6.8-fold higher than those achieved after oral dosing. Ketoprofen was detected in synovial fluid 1 hour after a single topical application but was not found in plasma samples. The authors suggested that intra-articular tissues, such as cartilage and menisci, may act as reservoirs for topically dosed NSAIDs and that topical application may allow an NSAID to achieve high intra-articular concentrations without substantial systemic exposure.25 The dose proportionality of diclofenac sodium 1% gel with respect to the amount of treated surface was accompanied by a pharmacodynamic dose-response relationship. Platelet aggregation, COX-1, and COX-2 were substantially inhibited by oral diclofenac sodium. The 2 topical regimens minimally affected platelet aggregation and inhibited COX-1 and COX-2 to a lesser extent than did oral diclofenac and in proportion to the treated skin surface area. Platelet function is generally not inhibited to a clinically relevant extent until COX-1 is 95% inhibited.26 The mean percentage inhibition of COX-1 on oral diclofenac was 76% with an SD of 20%, suggesting that a small number of participants experienced inhibition of COX-1 95% that could possibly have a clinically meaningful effect on COX-1-mediated functions. However, the mean percentage inhibition seen on either diclofenac sodium gel 1% treatment (treatment A, 8%; treatment B, 31%) was less than half of the 95% level considered necessary for COX-1 inhibition with the potential to affect platelet function, gastrointestinal protection, or maintenance of kidney function. Based on these findings,

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DICLOFENAC PHARMACOKINETICS topical diclofenac sodium gel 1% used at approved doses (maximum daily dose of 32 g) does not appear likely to affect COX-1-related functions. The degree of COX-2 inhibition in plasma was greater than COX-1 inhibition when diclofenac sodium gel 1% was applied to a single knee (median = 55% inhibition) or to both knees and hands (median = 90% inhibition) and when taken orally (median = 100%). This is consistent with the known role of COX-2 in the pain cascade and the necessity of inhibiting COX-2 to deliver pain relief. The fact that predose levels of COX-2 inhibition on day 7 were similar to 2-hour postdose levels for all 3 treatments may indicate that a steady-state effect on COX-2 was already reached after 6 days of treatment. The distribution of diclofenac sodium gel 1% to its site of action has not been well characterized. Topical therapy is expected to achieve higher diclofenac concentrations at the application site around the inflamed joint requiring treatment; COX-2 is induced at higher levels at this site compared with the systemic circulation.13,19 Therefore, although inhibition of COX-2 in plasma was greater following oral therapy, this does not necessarily predict the level of pain relief that is likely to occur after application of diclofenac sodium gel 1% relative to oral diclofenac. In addition, clinical studies of diclofenac sodium gel 1% have demonstrated efficacy in knee and hand OA using validated endpoints, thereby confirming the adequacy of COX-2 inhibition achieved with diclofenac sodium gel 1% at its site of action to treat the pain of knee and hand OA.23,27-29 In this study, AEs in general were reported by 30% to 46% of participants over the 7 days of dosing on each treatment, the most common being gastrointestinal. AEs potentially related to diclofenac treatment were infrequent and occurred in similar proportions (5%-8%) of participants across treatments. However, the types of AE suspected to be drug related following oral versus topical therapy differed qualitatively. With oral diclofenac, gastrointestinal disorders were believed to be drug related, whereas with diclofenac sodium gel 1%, treatment-related AEs were limited primarily to local reactions at the application site. The relatively low rate of gastrointestinal AEs with oral therapy may reflect the short duration of oral treatment in this study, whereas most local skin reactions would presumably be detected within 7 days of starting treatment with a topical therapy. Moreover, evidence suggests that the potential for morbidity from effects on the gastrointestinal system with oral dosing is greater than the potential for morbidity from local skin reactions with topical dosing.19 For example, in a 12-week study comparing topical and oral diclofenac formulations, patients who treated knee OA with a topical diclofenac solution experienced significantly fewer gastrointestinal AEs and severe gastrointestinal events compared with patients treated with oral diclofenac. Patients treated with oral diclofenac were also significantly more likely to have liver enzyme elevations and abnormalities in hemoglobin levels or creatinine clearance.18 It should be noted that despite a mean age of 59.9 years, the baseline renal function of all the included participants was normal and that no renal AEs were observed. Because of the short-term treatment delivered in this pharmacokinetic study, no specific renal monitoring was performed. The good renal safety of topical diclofenac was confirmed in a long-term safety study in knee OA patients.23 The overall tolerability of topical diclofenac sodium gel 1% observed in this study is generally consistent with results from longer studies. In 8- and 12-week clinical studies, topical diclofenac sodium gel 1% has shown safety and tolerability similar to a vehicle control, particularly with respect to gastrointestinal toxicity. Mild to moderate application site reactions have been the only category of AE with appreciably greater incidence in the topical diclofenac sodium gel 1% treatment groups.27-29 The long-term safety of diclofenac sodium gel 1% was demonstrated in a 12-month clinical trial.23 A few limitations need to be considered with respect to the validity of the study findings. This study was primarily a pharmacokinetic study and was therefore performed in normal, healthy volunteers following a crossover design. However, to approximate the general OA population, at least half of all participants had to be 60 years, and 50% to 70% had to be women. Despite these precautions, there may be differences between the included population (mean age of 59.9 5.7 [range, 50-74], normal mean body mass index, and 50% women) and those with OA: OA is more prevalent in the older age group and more common in women, and most OA patients are obese. By-gender analyses were performed on pharmacokinetics, from which no relevant gender effects were observed. Finally, in OA patients, an inflammatory process is ongoing, which may potentially alter diclofenac pharmacokinetics and pharmacodynamics, as COX-1 is constitutively expressed, but COX-2 is induced by inflammation. Moreover, both systemic and topical diclofenac are expected to achieve higher and prolonged diclofenac concentrations at effect sites around the inflamed joints requiring treatment.13,19 Additional considerations when evaluating the study include the selected crossover design that may

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KIENZLER ET AL potentially lead to a carryover effect of each therapeutic option and limitations of the ex vivo analyses of COX-1 and COX-2. Analyses of a potential carryover effect, which tested for the significance of the Period Treatment interaction, were conducted. The P values were generally quite high, .50 or greater, and therefore provide evidence that there was not a statistically significant carryover effect. The validated ex vivo method of using markers to assess COX-1 (TXB2) and COX-2 (PGE2) is preferred over in vitro analysis but does have some limitations.30,31 These markers evaluate systemic whole-blood samples and are most effectively used when highly standardized and the study includes a large number of patients, but there can still be biological variability in measurements.30-34 As noted in the pharmacodynamic results section, there were large standard deviations and ranges in predose and postdose values, including some negative values, particularly with the 2 topical treatments. These findings are representative of the difficulty to standardize topical dosing and of the variability known to occur between participants. Moreover, when assessed repeatedly in the same participants, lipopolysaccharide-induced PGE2 production at 24 hours showed intrasubject coefficient of variation (CV) of 20% to 30%.35 Thus, ex vivo methods may not be completely representative of in vivo activity, particularly in healthy volunteers.30,31,34 Despite these potential limitations, we believe that the pharmacokinetic and pharmacodynamic values and ratios observed in this study provide a relatively accurate characterization of the distribution and mechanism of action of topical diclofenac, as confirmed by the available diclofenac sodium gel 1% efficacy and safety studies.23,27-29 CONCLUSIONS In this study, overall and peak systemic exposure to diclofenac from diclofenac sodium gel 1% was significantly lower, and fluctuation in plasma levels was minimal compared with oral diclofenac sodium. Systemic exposure to diclofenac from diclofenac sodium gel 1% applied at a constant rate per cm2 of skin was roughly proportional to the treated skin surface. Diclofenac sodium gel 1% had a minimal effect on platelet aggregation, and levels of COX-1 inhibition were much lower than with oral diclofenac and proportional to the topical dose. Diclofenac sodium gel 1% application suppressed COX-2 appreciably, even at the lower diclofenac sodium gel 1% dose. Although AE rates were low and similar with diclofenac sodium gel 1% and oral diclofenac, only oral therapy was associated with treatment-related gastrointestinal AEs. This finding is consistent with the possibility that reduced systemic exposure to diclofenac during topical therapy may be associated with improved safety.
Financial disclosure: This study was sponsored by Novartis Consumer Health SA, Nyon, Switzerland.

REFERENCES
1. American College of Rheumatology. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000;43:1905-1915. 2. Jordan KM, Arden NK, Doherty M, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145-1155. 3. Pendleton A, Arden N, Dougados M, et al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2000;59:936-944. 4. Zhang W, Doherty M, Leeb BF, et al. EULAR evidence based recommendations for the diagnosis of hand osteoarthritisreport of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2007;66:377-388. 5. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage. 2007;15:981-1000. 6. Marnett LJ, Rowlinson SW, Goodwin DC, et al. Arachidonic acid oxygenation by COX-1 and COX-2: mechanisms of catalysis and inhibition. J Biol Chem. 1999;274:22903-22906. 7. Dannhardt G, Kiefer W. Cyclooxygenase inhibitors: current status and future prospects. Eur J Med Chem. 2001;36:109-126. 8. Lo V, Meadows SE, Saseen J. When should COX-2 selective NSAIDs be used for osteoarthritis and rheumatoid arthritis? J Fam Pract. 2006;55:260-262. 9. Motsko SP, Rascati KL, Busti AJ, et al. Temporal relationship between use of NSAIDs, including selective COX-2 inhibitors, and cardiovascular risk. Drug Saf. 2006;29:621-632. 10. Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol Suppl. 1998;51:8-16. 11. Tannenbaum H, Bombardier C, Davis P, et al. An evidencebased approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus Conference. J Rheumatol. 2006;33:140-157. 12. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med. 1999;106(5B):13S-24S. 13. Brune K. Persistence of NSAIDs at effect sites and rapid disappearance from side-effect compartments contributes to tolerability. Curr Med Res Opin. 2007;23:2985-2995.

60 J Clin Pharmacol 2010;50:50-61

DICLOFENAC PHARMACOKINETICS
14. Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs. 2000;60: 555-574. 15. Moore N. Diclofenac potassium 12.5mg tablets for mild to moderate pain and fever: a review of its pharmacology, clinical efficacy and safety. Clin Drug Investig. 2007;27:163-195. 16. Zacher J, Altman R, Bellamy N, et al. Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr Med Res Opin. 2008;24:925-950. 17. Magnette JL, Kienzler JL, Sallin D, et al. Diclofenac systemic exposure is not increased when topical diclofenac is applied to ultravioletinduced erythema. Eur J Clin Pharmacol. 2004;60:591-594. 18. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002-2012. 19. Zacher J, Burger K, Farber L, et al. Topical diclofenac Emulgel versus oral ibuprofen in the treatment of active osteoarthritis of the finger joints (Heberdens and/or Bouchards nodes): doubleblind, controlled, randomized study. Aktuel Rheumatol. 2001;26:7-14. 20. Voltaren Gel 1%. Parsippany, NJ: Novartis Consumer Health; 2007. 21. Kinlough-Rathbone R, Packham M, Mustard J. Platelet aggregation. In: Harder L, Zimmerman T, eds. Measurements of Platelet Function: Methods in Hematology. London: Churchill Livingstone; 1983:64-91. 22. Machin S, Mackie I. Platelet function tests. In: Chanarin I, ed. Laboratory Haematology: An Account of Laboratory Techniques. London: Churchill Livingstone; 1989:371-389. 23. Baraf H, Ramsay AJ, Schumacher D, et al. Long-term safety of diclofenac sodium gel 1% in patients with osteoarthritis of the knee [poster 430]. Presented at the 2007 World Congress on Osteoarthritis, Ft. Lauderdale, FL, USA, December 6-9, 2007. Osteoarthritis Cartilage. 2007;15(suppl C):C233. 24. Sioufi A, Pommier F, Boschet F, et al. Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel. Biopharm Drug Dispos. 1994;15:441-449. 25. Rolf C, Engstrom B, Beauchard C, et al. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology (Oxford). 1999;38:564-567. 26. Reilly IA, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood. 1987;69:180-186. 27. Altman R, Longley S, Rachidi S. Topical diclofenac sodium gel for knee osteoarthritis [poster 415]. Presented at the 2007 World Congress on Osteoarthritis, Ft. Lauderdale, FL, USA, December 6-9, 2007. Osteoarthritis Cartilage. 2007;15(suppl C):C225. 28. Altman R, Zacher J, Dreiser RL. Efficacy and safety of diclofenac sodium gel 1% in patients with OA of the hand: a prospective, 8-week, randomized, double-blind, vehicle-controlled, multicenter, phase 3 trial [poster 288]. Presented at: American College of Rheumatology Annual Meeting; November 6-11, 2007; Boston, MA. 29. Barthel HR, Haselwood D, Parikh P, et al. Efficacy and safety of diclofenac sodium gel 1% in patients with OA of the knee: a prospective, 12-week, randomized, double-blind, vehiclecontrolled, multicenter, phase 3 trial [poster 289]. Presented at: American College of Rheumatology Annual Meeting; November 6-11, 2007; Boston, MA. 30. Cronstein BN. Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. Cleve Clin J Med. 2002;69: S13-S19. 31. Huntjens DRH, Danhof M, Della Pasqua OE. Pharmacokineticpharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology. 2005;44:846-859. 32. Lipsky LPE, Abramson SB, Crofford L, et al. The classification of cyclooxygenase inhibitors. J Rheumatol. 1998;25:2298-2303. 33. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104:413-421. 34. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:433-442. 35. Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.J Pharmacol Exp Ther. 1994;271:1705-1712.

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