Drug Invest.

4 (5): 435-440, 1992

0114-2402/92/0005-0435/$03.00/0
© Adis International Limited. All rights reserved.
ORI1212

Piroxicam Plasma Concentrations Following Repeated

Topical Application of a Piroxicam 0.5% Gel
J.B. Fourtillan and J. Girault
Centre de Recherche CEMAF, Poi tiers, France

Summary The pharmacokinetic parameters of a piroxicam 0.5% topical gel were determined in 20 healthy
volunteers (6 women and 14 men) following application of mUltiple doses (20mg piroxicam daily)
over 14 days. 21 blood samples were drawn from each patient beginning just before application
of the first dose, with the final sample taken 14 days after application of the last dose. Plasma
concentrations of piroxicam were determined by high-performance liquid chromatography using
UV detection at 340nm. There was considerable interindividual variation in piroxicam half-lives
with a mean of 79 hours. Mean piroxicam plasma concentrations at steady-state were between
300 and 400 ng/ml, which is about 5% of those observed after equivalent doses of oral or intra-
muscular piroxicam. No adverse experiences were reported during the study period. Thus, the
results of this study confirm the minimal systemic absorption of piroxicam during multiple-dose
application of the 0.5% topical gel and the excellent tolerability ofthis mode ofpiroxicam therapy.

Piroxicam, an effective and well tolerated non-
steroidal anti-inflammatory drug (NSAID), has
been available for oral, parenteral and rectal
administration for a number of years. The intro-
duction of a piroxicam 0.5% gel provides a con-
venient alternative for patients with painful and
inflammatory musculoskeletal conditions amena-
ble to topical drug therapy. Theoretical advantages
of local application of piroxicam include targeting
the site of action while minimising systemic blood
concentrations and potential adverse effects. Phar-
macokinetic data indicate that topically applied pi-
roxicam gel is absorbed percutaneously.
Following application of a single dose of gel, de-
tectable concentrations of piroxicam were achieved
in synovial fluid and synovial membranes 2 to 24
hours after the application (Sugawara et al. 1984).
Throughout the sampling period, piroxicam con-
centrations in synovial fluid approximated those of
plasma; however, at early time points, synovial fluid
levels were sometimes higher and at later time
points tended to be lower than those in plasma.
Piroxicam concentrations in synovial membrane
were higher than those in synovial fluid in the ma-
jority of cases.
Kanazawa and colleagues (1987) showed that
following a single application of 3g piroxicam 0.5%
gel (15mg piroxicam), the drug was gradually ab-
sorbed percutaneously, achieving a serum concen-
tration which peaked at approximately one-
fifteenth of that observed after administration of a
20mg capsule (adjustment was made for dose). In
clinical practice, patients apply piroxicam gel sev-
eral times daily for an extended period depending
on the disorder being treated. The purpose of the
present study was to determine the pharmacokin-
etic parameters resulting from repeated applica-
tions of piroxicam 0.5% topical gel for 14 days
436
Table I. Characteristics of the subjects
No. of men/women 6/14
Age (y)
Mean ± SEM 24 ± 1
Range 18-30
Weight (kg)
Mean ± SEM 62 ± 2
Range 45-75
Height (em)
Mean ± SEM 173 ± 2
Range 156-185
which more closely simulates use of the drug in the
clinical setting.
Methods
Before the start of the study, the protocol was
approved by the Local Ethical Committee. 20
healthy volunteers (6 women and 14 men) ranging
in age from 18 to 30 years (mean 24) underwent a
clinical examination, including routine blood tests
and urinalysis, and gave informed consent prior to
participating in this study (table I). Patients were
excluded if they had an abnormal physical exam-
ination, a serious medical or surgical history,
clinically significant abnormal laboratory values,
or had taken any medication within 15 days prior
to study entry. Women were not admitted to the
trial if they were pregnant or nursing or intended
becoming pregnant while or for a period of 4 weeks
after receiving the study drug.
All study subjects applied 2g of piroxicam 0.5%
gel (IOmg piroxicam) twice daily (at 8am and at
8pm) for 14 consecutive days. The gel was applied
bilaterally to the external surfaces of the deltoid
muscles using 2.5ml Eppendorf® Combitips. Each
cutaneous application zone comprised a surface
area of l13cm 2 , and the gel (lg) was massaged into
the skin of each muscle for approximately 3 min-
utes with a finger covered by a rubber finger stall
so that no surface residue remained. Following an
overnight fast, all participants received the first ap-
plication of piroxicam gel in the clinic in the pres-
ence of the investigator. Before application of the
Drug Invest. 4 (5) 1992
first dose of gel, the skin was washed with soap and
water. Subsequent applications were made by the
study subjects at home. Participants were in-
structed not to wash the application zones for 4
hours after application of the gel.
21 blood samples were collected from time zero
(defined as the time just before the first application
on day 1) to 336 hours after the last application on
day 14 (day 28) [see fig. 1]. On the days of blood
sampling, the piroxicam gel was applied after the
blood sample was obtained. Plasma concentrations
of piroxicam were determined by high-perform-
ance liquid chromatography (HPLC) using UV de-
tection at 340nm (Fourtillan et al. 1985). The tech-
nique used was accurate and precise down to a
piroxicam concentration of 5 ng/ml.
Piroxicam was separated from endogenous
compounds by a liquid extraction method prior to
the determination (Fourtillan & Dubourg 1983). A
flumequine solution was used as the internal stand-
ard for HPLC determinations. A standardisation
range of 10 piroxicam concentrations was prepared
on each day analyses were performed. The stan-
dardisation curves were linear over the range of 0
to 1250 ng/ml.
Pharmacokinetic Analysis
The repeatability tests, conducted on a series of
control plasma samples supplemented by known
quantities of piroxicam (4.9, 39.1 and 625 ng/ml),
showed that the method is correct and precise. The
percentage error and coefficient of variation ob-
served at the limit of detection (4.9 ng/ml) were 9
and 20%, respectively. The method described for
the determination of piroxicam in plasma was ap-
plied without constant systematic error but with a
small proportional error of 10.34%.
Pharmacokinetic data were computed using the
PHARM program on a Hewlett Packard HP900
unit (Gomeni 1983). Pharmacokinetic parameters
ofpiroxicam 0.5% topical gel were calculated based
on minimum plasma drug concentrations observed
just before each gel application, and on the pirox-
icam plasma concentration vs time curve obtained
after the last gel application according to the sam-
Piroxicam Gel 437

I Day 1 I Day 2-Day 3 I Day 4 - - - - - - - - - - - Day 81 Day 9 I I

Day 10 Day 11 I Day 12

220
Time (h) o4 12 24 72 168 192 218 228 240 264

Plasma
II I
Po P2
I I
P3
I
P4
I
Ps
II I
Ps P8
I
Pg
I
P10
--
samples P7
t1
10mg piroxicam (first dose)

I Day 13 1 Day 141 Day 151 Day 16 1Day 111 Day 18 Day 20 I Day 21 Day 28 I
316
Time (h) 288 312 324336 360 384 408 480 648
I II I I I I I I I
Plasma Pll P12 P14 P1S P16 PH P18
samples
[13

10mg piroxicam (last dose)

Fig. 1. Schedule of blood samples to determine the pharmacokinetic parameters of piroxicam 0.5% gel. All subjects applied
2g piroxicam gel (lOmg piroxicam) twice daily for 14 days.

piing protocol described above. The terminal log-
linear phase of the piroxicam plasma concentra-
tion-time curve following the final application of
the gel on day 14 (312 hours after the first dose)
was plotted for each subject. The apparent elim-
ination half-life (t'l,) of piroxicam was determined
from data observed after the last gel application by
regression analysis on the terminal phase of the
semilogarithmic plasma concentration vs time plot.
The apparent total clearance (CL/F) of piroxi-
cam was calculated from the formula:
CL/F = DoselT X l/Cpss
where T represents the time interval between 2 suc-
cessive gel applications (dosing interval) and CPss
is the mean piroxicam plasma concentration at
steady-state.
Results
Each study participant had a normal physical
examination, with no significant medical or sur-
gical history, and did not receive any medications
for 15 days before entry into the study. The study
group was homogeneous with respect to race (all
Caucasians), weighing an average of 62kg (range:
45 to 75kg) with a mean height of 173cm (range:
156 to 185cm) [table I).
Table II presents the mean piroxicam plasma
concentrations (± SEM) over time while figure 2
depicts these graphically. Piroxicam concentra-
tions increased slowly during the course of gel ap-
plication, reaching mean values of over 200 ngjml
on study day 4, but values less than 400 ngjml by
day 14. Average steady-state piroxicam plasma
concentrations ranged between 300 and 400 ngjml.
There was considerable interindividual variation
in piroxicam elimination half-lives with values
ranging from 36.17 to 297.41 hours. The calculated
mean value was 78.9 ± 12.52 hours.
No local or systemic adverse effects were ob-
served by the investigator or reported by the sub-
jects for the entire duration of the study.
As stated above, mean plasma piroxicam con-
centrations at steady-state were between 300 and
400 ngjml. Furthermore, since the apparent t'l, of
438 Drug Invest. 4 (5) 1992

Table II. Mean piroxicam plasma concentrations (Aoki et al. 1984; Fujimaki et al. 1984; Kageyama
1987; Kroll et al. 1989; Sugioka et al. 1984).
Study Time Mean conc. SEM
day (h) (ng/ml)
Following application of the gel preparation, ab-
sorption occurs and detectable piroxicam concen-
0.0 0.0 0.0 trations are measured in synovial fluid and syn-
4.0 5.8 2.0 ovial membrane (Sugawara et al. 1984).
12.0 27.3 10.8
4 72.0 130.9 16.8
Results of clinical studies involving large num-
8 168.0 233.8 31.7 bers of patients with both acute and chronic con-
9 192.0 262.8 40.4 ditions confirm that piroxicam gel is more effec-
10 216.0 267.3 39.1 tive than placebo (Aoki et al. 1984; Fujimaki et al.
220.0 288.6 44.4
1984; Kageyama 1987) and at least as effective as
228.0 311.6 47.2
11 240.0 292.6 37.1
topical gel formulations of indomethacin (Aoki et
12 264.0 309.6 46.2 al. 1984; Fujimaki et al. 1984; Sugioka et al. 1984)
13 288.0 324.2 45.0 and diclofenac (Kroll et al. 1989). The results of
14 312.0 315.1 43.3 these studies also indicate that topical piroxicam
316.0 370.4 56.1
is as well tolerated as placebo, is better tolerated
324.0 367.8 48.6
15 336.0 298.9 44.1
than indomethacin gel, and is comparable to di-
16 360.0 253.8 39.4 clofenac gel. It is notable that the majority of ad-
17 384.0 194.9 37.5 verse experiences reported by patients receiving pi-
18 408.0 159.8 34.7 roxicam gel were mild or moderate and that there
21 480.0 90.6 23.1
were no gastrointestinal complaints. The lack of
29 648.0 30.7 19.3
systemic adverse events may be related to the low
plasma concentrations achieved after local appli-
cation. Data from single-dose pharmacokinetic
the gel (78.9 hours) is considerably longer than the studies confirm that systemic absorption of locally
dose interval (12 hours), steady-state plasma pi- applied piroxicam is substantially lower than that
roxicam concentrations would be expected to re- of oral or intramuscular piroxicam. Thus, it ap-
main essentially constant with only slight differ- pears that efficacy and tolerability data from clinical
ences between the maximum and minimum plasma trials as well as data from single-dose pharmaco-
levels. This was indeed confirmed by measuring kinetic studies are consistent with the proposed
plasma piroxicam concentrations at the time of the theoretical advantages of locally applied piroxicam
final application of the gel and 4 and 12 hours later. gel.
Plasma levels at each time were in the range of 350 In the present study, the pharmacokinetic para-
ng/ml, and this value was thus substituted for CPss. meters of piroxicam are reported following multi-
Therefore, the apparent total clearance of piroxi- ple applications of piroxicam 0.5% topical gel,
cam gel was calculated as: which more closely simulates its actual usage in the
clinical setting. Piroxicam plasma concentrations
CL/F = Dose/r X I/Cpss =
increased gradually during the course of multiple
20mg/12h X 1/350 ngfml = 4.76 L/h.
applications of piroxicam gel. The average steady-
state plasma concentrations achieved were in the
Discussion range of 350 ngfml, or about 5% of those observed
in subjects receiving oral or intramuscular piroxi-
Piroxicam 0.5% topical gel provides a conven- cam 20mg daily (Fourtillan 1987).
ient alternative for certain patients with acute or The apparent mean tlh was 79 hours. This is
chronic painful and inflammatory musculoskeletal longer than that reported in the single-dose study
conditions amenable to local percutaneous therapy (40 hours) of Kanazawa et al. (1987), but there was
Piroxicam Gel 439

1000

• I"-'I. W
E
c;
.s. 100
I:
0

~
!
Ql
U
I:
8
E
'"x
.2 10
e
a:

0.0 3.0 6.0

Time (days)

Fig. 2. Semilogarithmic plot of the mean piroxicam plasma concentration as a function of time.

considerable interindividual variation in the pre-
sent study. This may have been due to differences
among subjects in terms of tissue accumulation and
diffusion of drug. Moreover, 79 hours is still within
the reported range (27 to 89 hours) for oral pirox-
icam (Hobbs 1983). Based on the calculation of the
apparent t'l2 of piroxicam in this study, it is pos-
sible to estimate the time required to reach steady-
state during administration of the piroxicam gel.
For practical purposes, it can be assumed that 3.3
half-lives, or about 11 days, are required to achieve
steady-state. Since the half-life is relatively long and
the recommended dosage is 3 to 4 applications daily
based on previous clinical trials (e.g. Kageyama
1987; Sugioka et at 1984), constant piroxicam con-
centrations are maintained.
Comparison of the apparent total clearance of
the gel calculated in this study (4.76 L/h) with that
of the other piroxicam formulations reported in
previous studies enables an estimation of the bio-
availability of piroxicam in gel form. Based on data
from an earlier study involving oral and intra-
muscular piroxicam (Fourtillan et a1. 1985), we es-
timated an apparent total clearance of 0.14 L/h or
2.15 ml/h. This value is in agreement with those
published by other authors (2.94, 1.8 and 2.08 ml/
h/kg; Ishizaki et aI. 1979; Rogers et a1. 1981; Til-
stone et a1. 1981). It is therefore suggested that the
bioavailability of piroxicam via the percutaneous
route relative to the amount bioavailable by mouth
or by intramuscular injection is of the order of 0.14/
4.76 or 3%.
These findings are consistent with the results of
other studies which determine the pharmacokin-
etic characteristics of various NSAID topical prep-
arations. In general, serum drug concentrations and
relative bioavailability are low. The maximum
plasma ibuprofen concentration following a single-
dose application of 400mg ibuprofen gel was 200
ng/ml or about 1/50 of the minimum therapeutic
level following oral therapy (Berner et a1. 1989).
Application of single Ig doses of a 5% and 10%
naproxen gel yielded maximum serum naproxen
concentrations of 42 ng/ml and 40 ng/ml, respec-
tively (van den Ouweland et a1. 1989). The cal-
culated bioavailability based on serum and urine
440
levels was approximately 1% for the 10% naproxen
gel and 2% for the 5% gel. Flunoxaprofen was not
detected in serum following a single application of
125mg of a gel preparation (Bareggi et al. 1988).
Multiple-dose studies involving a ketoprofen gel
and a diclofenac gel also revealed that very little
drug enters the systemic circulation. Plasma ke-
toprofen concentrations following application of
approximately 80mg daily for 3 days were 6.3, 18.2
and 18.0 ng/ml at 2, 6 and 12 hours after the last
dose (Ballerini et al. 1986). Topical application of
a larger dose (375mg - as a single dose for 2 days,
then in 2 divided doses for 10 days) of ketoprofen
gel resulted in a maximum plasma ketoprofen con-
centration of 294 ng/ml and an elimination tl/2 of
17 hours (Flouvat et al. 1989). The estimated bio-
availability of ketoprofen gel was of the order of
5%. The plasma concentration of diclofenac fol-
lowing application of 80mg in a gel preparation 3
times daily for 4 days was 40.6 ng/ml (Rader-
macher et al. 1991).
Conclusion
This study further confirms the observation that
only a relatively small proportion ofa dose of top-
ically applied piroxicam gel reaches the systemic
circulation when compared with oral or intramus-
cular formulations. This was true even with mul-
tiple applications of the gel. The lack of adverse
effects seems to support the excellent tolerability
of the piroxicam gel preparation.
References
Aoki T, Numajiri M, Yamamoto M, et al. Comparative study of
piroxicam gel with indomethacin gel and piroxicam placebo
gel in the treatment of pain from orthopedic trauma. Yakuri
to Chiryo 12: 101-117, 1984
Ballerini R, Casini A, Chinol M, Mannucci C, Giaccai L, et aI.
Study on the absorption of ketoprofen topically administered
in man: comparison between tissue and plasma levels. Inter-
national Journal of Clinical Pharmacology Research 6: 69-72,
1986
Bareggi SR, Pedrazzini S, De Angelis M. Pharmacokinetic study
in man with the non-steroidal antiinflammatory drug flunox-
aprofen. Serum concentration-time profile after oral or topical
preparations. Arzneimittel-Forschung 38: 574-577, 1988
Berner G, Engels B, Vogtle-Junkert U. Percutaneous ibuprofen
Drug Invest. 4 (5) 1992
therapy with Trauma-Dolgit gel: bioequivalence studies. Drugs
under Experimental and Clinical Research 15: 559-564, 1989
F10uvat B, Roux A, Delhotal-Landes B. Pharmacokinetics ofke-
toprofen in man after repeated percutaneous administration.
Arzneimittel-Forschung 39: 812-815, 1989
Fourtillan JB. Pharmacokinetics of intramuscular piroxicam.
European Journal of Rheumatology and Inflammation 8: 38-
41, 1987
Fourtillan JB, Dubourg D. Pharmacokinetic study of piroxicam
after a single 20mg oral dose administered to healthy adults.
Therapie 38: 163-170, 1983
Fourtillan JB, Mignot A, Bertin E, et al. Bioavailability study of
two pharmaceutical formulations of piroxicam: 20mg capsules
and a solution for 1M injection (20mg ampoules) following
multiple dosing of 40mg the first two days and 20mg on five
subsequent days. Data on file, Pfizer International, New York,
1985
Fujimaki E, Ohno M, Nagashima K, et al. Clinical evaluation of
piroxicam gel versus indomethacin gel and placebo gel in the
treatment of muscle pain: a double-blind multicenter study.
Yakuri to Chiryo 12: 119-137, 1984
Gomeni R. An interactive program for individual and population
estimation. In Von Bommel et al. (Eds) Medinfo 83, pp. 1022-
1025, North Holland, 1983
Hobbs DC. Pharmacokinetics of piroxicam in man. European
Journal of Rheumatology and Inflammation 6: 46-55, 1983
Ishizaki T, Nomura T, Abe T. Pharmacokinetics of piroxicam, a
new nonsteroidal anti-inflammatory agent, under fasting and
post prandial states in man. Journal of Pharmacokinetics and
Biopharmaceutics 7: 369-381, 1979
Kageyama T. A double-blind placebo controlled multicenter study
of piroxicam 0.5% gel in osteoarthritis of the knee. European
Journal of Rheumatology and Inflammation 8: 114-115, 1987
Kanazawa M, Ito H, Shimooka K, Mase K. The pharmacokin-
etics of 0.5% piroxicam gel in humans. European Journal of
Rheumatology and Inflammation 8: 117, 1987
Kroll MP, Wiseman RL, Guttadauria M. A clinical evaluation of
piroxicam gel: an open comparative trial with diclofenac gel
in the treatment of acute musculoskeletal disorders. Clinical
Therapeutics II: 382-391, 1989
Radermacher J, Jentsch D, Scholl MA, Lustinetz T, Frolich Je.
Diclofenac concentrations in synovial fluid and plasma after
cutaneous application in inflammatory and degenerative joint
disease. British Journal of Clinical Pharmacology 31: 537-541,
1991
Rogers HJ, Spector RG, Morrison PJ, et al. Comparative steady
state pharmacokinetic study of piroxicam and flurbiprofen in
normal subjects. European Journal of Rheumatology and In-
flammation 4: 303-308, 1981
Sugawara S, Ohno H, Ueda R, et al. Studies of percutaneous ab-
sorption and tissue distribution of piroxicam gel. Journal of
Medicinal and Pharmaceutical Science 12: 1233-1238, 1984
Sugioka Y, Muraoka Y, Takagishi K, et al. Multicenter clinical
evaluation of piroxicam gel versus indomethacin gel in the
treatment of non-traumatic diseases of tendon or muscle. Yak-
uri to Chiryo 12: 139-153, 1984
Tilstone WJ, Lawson DH, Omara F, et al. The steady-state phar-
macokinetics of piroxicam: effect of food and iron. European
Journal of Rheumatology and Inflammation 4: 309-313,1981
Van den Ouweland FA, Eenhoorn PC, Tan Y, Gribnau FWJ.
Transcutaneous absorption of naproxen gel. European Journal
of Clinical Pharmacology 36: 209-211, 1989
Correspondence and reprints: Dr J.B. Fourtillan. Centre de Re-
cherche CEMAF, 144, rue de la Gibauderie, 86000 Poitiers, France.