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Systemic Bioavailability of Topical Diclofenac

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 The Journal of Clinical
Pharmacology http://jcp.sagepub.com/

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 19 October 2009
DOI: 10.1177/0091270009336234

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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 tab-
lets 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,
N 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 through-
out the body under normal conditions. The gastroin-
testinal 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
50 J Clin Pharmacol 2010;50:50-61
Downloaded from jcp.sagepub.com at Novartis Global on February 15, 2013
Pharmacokinetics
title
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 gastro-
intestinal 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 topi-
cal diclofenac were less pronounced.
Keywords:Diclofenac; absorption; bioavailability; phar-
macokinetics; pharmacodynamics
Journal of Clinical Pharmacology, 2010;50:50-61
2010 the American College of Clinical Pharmacology
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 avail-
able in oral formulation since 1983 and topical for-
mulation 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
 DICLOFENAC PHARMACOKINETICS
Diclofenac sodium gel 1% is a new topical formula-
tion, 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 pro-
tocol for the study was approved by the Institutional
Review Board (IRB) of the clinical center that con-
ducted 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 par-
ticipants 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 replace-
ment therapy or contraceptives; or if they were preg-
nant or had any active clinically relevant disorder
that might compromise patient welfare or confound
the study results.
Pharmacokinetics 51
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Interventions
The investigational therapy was topical diclofenac
sodium gel 1%, and the reference therapy was dic
lofenac sodium enteric-coated 50-mg tablets. Par
ticipants 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 consist-
ing 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 treat-
ment 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 approxi-
mately 400 cm2 of skin. For treatment B, partici-
pants 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 applica-
tion 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 FDA-
approved maximum daily dose of 32 g gel. For treat-
ment 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 par-
ticipants at home. On day 7, all doses were super-
vised at the clinical center.
 KIENZLER ET AL
Figure 1. Study design.
Storage conditions for each study drug were des
cribed on the label. Medications were administered
open label; however, the analytical laboratory rem
ained 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 treat-
ments. The pharmacokinetic sampling plan is sum-
marized 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 quantifica-
tion of 0.5 ng/mL (plasma) and 3 ng/mL (urine).
52J Clin Pharmacol 2010;50:50-61
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The following pharmacokinetic parameters were
calculated for each participant:
Day 1, treatment Bthe area under the plasma concen-
tration 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
4OH-diclofenac
Day 7, all treatmentsminimum concentration (Cmin); max-
imum 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 4OH-diclofenac
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 fol-
lowed 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 measur-
ing 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 ship-
ment 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 immu-
noassay 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 col-
lected 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 treatment-
emergent AEs (coded according to the Medical Dic
tionary 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 relation-
ship 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
A 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 day7; in the
morning of study days 70 1, 77 1,
and 84 1 when treatment A was
given in period 3.
B 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.
C Immediately before the first dose on
days 1, 2, and 5 to 7 and at the fol-
lowing 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 adminis-
tration), 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; treat-
ment C = diclofenac sodium 50-mg tablets.
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 treat-
ment. Differences of least squares (LS) means (bet
ween 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 ass
essed 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 expo-
nentiating 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 4OH-diclofenac separately for treatments A
and B.
Pharmacokinetics 53
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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 aggre-
gation 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 exces-
sive departure from normality, the median value
was used to summarize inhibition of PGE2, and dif-
ferences between treatments in inhibition of PGE2
were tested with the nonparametric Wilcoxon
signed rank test.
RESULTS
Participants
Of 94 participants screened, 18 were deemed ineligi-
ble 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 par-
ticipants are summarized in Table II.
Thirty-nine participants (98%) completed the
study. One participant on sequence C-A-B discontin-
ued for personal reasons after the morning tablet
intake on day 6 of period 1 (treatment C). Of 25 par-
ticipants who received treatment A or B during
period 3, 22 (88%) agreed to participate in the
f ollow-up part of the study. All 39 participants who
completed the study were fully compliant with dos-
ing 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, treat-
ment 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
 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 par-
ticipants 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 sam-
pled 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 differ-
ence in application site area, diclofenac plasma con-
centrations on day 7 for treatment B were
approximately 3-fold higher than those for treatment
A. For treatment A, mean day 7 diclofenac concen-
trations 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% applica-
tion. For treatment C, mean day 7 diclofenac con-
centrations 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 immedi-
ately 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 approxi-
mately 150-fold higher than for treatment A and
40-fold higher than for treatment B. The peak-trough
fluctuation was approximately 100% for both topi-
cal treatments and approximately 1500% for the
54J Clin Pharmacol 2010;50:50-61
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Table II Demographic Characteristics
of the Study Population
All Participants (N = 40)
Men, % 50.0
White, % 100
Mean (SD) age, y 59.9 (5.7)
Range 50-74
Mean (SD) weight, kg 74.2 (12.3)
Range 52-103
Mean (SD) height, cm 169.7 (9.3)
Range 147-187
Mean (SD) BMI, kg/m2 25.6 (2.7)
Range 20.4-33.0
BMI, body mass index.
oral treatment. The greater differences in Cmax and
peak-trough fluctuation seen with treatment C com-
pared with A or B are consistent with the clear
postdose peaks that were seen after oral administra-
tion 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 expo-
sure 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 ther-
apy. 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 treat-
ment B accumulated to a moderate extent in plasma.
The first mean plasma level of diclofenac above the
lower limit of quantification occurred 2 hours follow-
ing 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 Summary of Day 7 Plasma Pharmacokinetic Parameters

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

A (n = 39) 15.0 7.33 14 (0-24) 233 128 5.92 3.65 9.70 5.32 95.6 40.4
B (n = 39) 53.8 32.0 10 (0-24) 807 478 19.2 12.1 33.6 19.9 106 51.6
C (n = 39) 2270 778 6.5 (1-14) 3890 1710 5.70 3.11 162 71.2 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 Excretion and Urine Pharmacokinetics

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 mea-
surable plasma diclofenac levels 28 days post-
treatment 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 par-
ticipants had a measurable diclofenac concentra-
tion (0.8 ng/mL).
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 treat-
ments 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

Pharmacokinetics 55

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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 349 (302-403) 340 (294-394) 273 (224-332) 250 (207-302)
Treatment A/treatment C 0.63 (0.548-0.733) 5.79 (5.00-6.70) 2.51 (2.06-3.06) 2.21 (1.82-2.68)a
Treatment B/treatment C 2.21 (1.91-2.56) 19.70 (17.0-22.8) 6.85 (5.63-8.34) 5.52 (4.56-6.69)a
Day 7/day 1 ratio, %
Treatment A 493 (417-581) 666 (561-790)
Treatment B 417 (367-474) 285 (248-327) 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 Ae0-24 4-OH-Diclofenac, g

Treatment Day 1 Day 7 Day 1 Day 7

A (n = 39) 64.1 64.1 265 164 95.0 85.5 539 332

B (n = 39) 249 118 672 300 333 160 1270 602
C (n = 39) 10300 3980 23400 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 treat-
ments 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 accumula-
tion 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 aggrega-
tion was minimally affected by either topical treat-
ment. Oral diclofenac inhibited platelet aggregation to
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 rela-
tively 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 inhibi-
tion 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 stand-
ard deviations of mean TXB2 percent inhibition values
(both predose and postdose) were relatively large.
Differences in COX-1 inhibition were statistically sig-
nificant 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 inhibi-
tion of the COX-2 enzyme. Median COX-2 inhibition

56J Clin Pharmacol 2010;50:50-61

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 DICLOFENAC PHARMACOKINETICS

Table VI Summary of Percentage Inhibition of Pharmacodynamic Parameters, Day 7 (vs Screening)

Platelet
Aggregation Platelet
(Arachidonic Aggregation
Acid) (ADP 5 M) TXB2 (COX-1) PGE2 (COX-2)

Treatment 2 Hours Postdose 2 Hours Postdose Predose 2 Hours Postdose Predose 2 Hours Postdose

A (n = 39) 8.9 21.9 a

0.3 19.6 b
17.9 63.4 c
8.16 73.8 c
58.6 (393; 100) 55.5 (724; 100)
B (n = 39) 11.1 45.4c 3.0 20.4d 35.1 36.1c 30.9 32.4c 90.7 (184; 100) 89.8 (25.0; 100)
C (n = 39) 63.4 46.5c 13.5 20.4d 37.3 34.0c 76.4 20.0c 99.8 (64.6; 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) Day 7 .79 <.001 <.001

Platelet aggregation (ADP 5 M) Day 7 .29 .003 <.001
TXB2 (COX-1) Day 7, predose .012 .005 .76
Day 7, 2 hours postdose .014 <.001 <.001
PGE2 (COX-2) Day 7, predose <.001 <.001 <.001
Day 7, 2 hours postdose <.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 signifi-
cantly 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 aggrega-
tion 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 treat-
ment 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 treat-
ment B. The most common category of AEs was gas-
trointestinal, 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 dif-
fered between topical diclofenac sodium gel 1% and
oral diclofenac. Potentially treatment-related AEs

Pharmacokinetics 57

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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 poten-
tially 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 rele-
vant changes in vital signs, and no emergent abnor-
malities 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 sys-
temic 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 through-
out the day. Constant plasma levels following
diclofenac sodium gel 1% treatment suggest that topi-
cally administered diclofenac accumulates in the skin
and/or underlying periarticular and articular tissues,
from which it is slowly released into the systemic cir-
culation. 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
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steady decline in diclofenac plasma levels, with essen-
tially 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 adminis-
tered 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 elimina-
tion.24 In another study, ketoprofen concentrations in
plasma, synovial fluid, and intra-articular tissue were
compared after administration of a single 30-mg keto-
profen plaster, multiple plaster applications over a
5-day period, or a single oral 50-mg tablet in 100
patients undergoing knee arthroscopy. Ketoprofen con-
centrations in the meniscus and cartilage were 2- to
3-fold higher than those in plasma, and median con-
centrations 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 topi-
cally dosed NSAIDs and that topical application may
allow an NSAID to achieve high intra-articular concen-
trations 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 gener-
ally not inhibited to a clinically relevant extent until
COX-1 is 95% inhibited.26 The mean percentage inhi-
bition of COX-1 on oral diclofenac was 76% with an
SD of 20%, suggesting that a small number of partici-
pants experienced inhibition of COX-1 95% that
could possibly have a clinically meaningful effect on
COX-1-mediated functions. However, the mean per-
centage inhibition seen on either diclofenac sodium
gel 1% treatment (treatment A, 8%; treatment B, 31%)
was less than half of the 95% level considered neces-
sary for COX-1 inhibition with the potential to affect
platelet function, gastrointestinal protection, or main-
tenance of kidney function. Based on these findings,
 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 treat-
ments may indicate that a steady-state effect on
COX-2 was already reached after 6 days of treat-
ment. 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 inhi-
bition 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 gastrointesti-
nal. 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 treat-
ment in this study, whereas most local skin reactions
would presumably be detected within 7 days of start-
ing treatment with a topical therapy. Moreover, evi-
dence 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
Pharmacokinetics 59
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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 gastroin-
testinal toxicity. Mild to moderate application site
reactions have been the only category of AE with
appreciably greater incidence in the topical dic
lofenac 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 fol-
lowing a crossover design. However, to approximate
the general OA population, at least half of all partici-
pants had to be 60 years, and 50% to 70% had to be
women. Despite these precautions, there may be dif-
ferences 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 com-
mon in women, and most OA patients are obese.
By-gender analyses were performed on pharmacoki-
netics, 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
 KIENZLER ET AL
potentially lead to a carryover effect of each therapeu-
tic 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 sig-
nificant 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 biologi-
cal variability in measurements.30-34 As noted in the
pharmacodynamic results section, there were large
standard deviations and ranges in predose and post-
dose values, including some negative values, particu-
larly 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 coef-
ficient 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 mech-
anism 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 signifi-
cantly 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 sur-
face. 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 propor-
tional 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 associ-
ated with treatment-related gastrointestinal AEs. This
60J Clin Pharmacol 2010;50:50-61
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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.
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