A COMPARATIVE STUDY IN
PRESENCE AND ABSENCE OF
PETHIDINE AFTER SURGERY
Objectives
1. Pharmacokinetic parameters of ketoprofen
after orthopedic surgery.
2. Effect of concomitant administration of
pethidine on PK of ketoprofen.
3. Comparison with published data.
Objectives
4. Effect of age on PK of ketoprofen.
5. Assessment of pain relief in ketoprofen
compared to ketoprofen plus Pethidine.
Introduction
What is Ketoprofen ? •
What is Pethidine ? •
Uses of Ketoprofen •
Interactions •
Introduction
Mode of action
Mambrane phospholipids
Arachidonic acid
Lipoxygenase
HETE
LT
Cyclooxygenase
PG
TX
Introduction
Literature Review
Equivalent to indomethacin, 70x more potant •
than aspirin, more potent than naproxen.
Guyonnet etal 1976
Nimesulide similar to ketoprofen in ENT •
surgery.
Coscarelli etal 1993
Introduction
Literature Review
NSAIDs exert an antiproliferative effect •
against human colon cancer cells.
Hixoson etal 1994
Sulindac & ketoprofen are potent as •
inhibitors of urinary bladder carcinogenesis.
Kandal etal 1996
Introduction
Literature Review
Ketoprofen required least intervention analgesia •
followed by buprenorphine then pethidine in
ovariohysterectomy.
Slingsby etal 1998
Pain releif last longer with ketoprofen than with •
pethidine in joint surgery.
Langlais etal 1987
Introduction
Literature Review
Ketoprofen associated with faster recovery •
from anaesthesia & required less postoperative analgesia compared to pethidine
after nasal surgery.
Elhakeem etal 1991
Methodology
1. Demographic data
Methodology
2. Exclusion & Inclusion Criteria
1. Allergy to ketoprofen
2. CV, Respiratory, GI, neurologic dysfunction
3. Using other NSAIDs within one week
4. Drugs interfered with the analysis
5. Normal CBC, electrolytes
Methodology
1. Chromatographic conditions
Mobile phase: 50% methanol, 50% •
deionized water, 2 ml glacial aa…PH=5
Flow rate: 2 ml / min •
 max: 254 nm •
Attenuation: 0.05 •
2. Apparatus
Pump: model 501 •
Injector: model 717 •
Integrator: model 746 •
Detector: model 484 •
C18 cartidge (15 cm  Bonda pack) •
3. Validation
Range of St. curve: 50 ng/ ml - 4 g/ml •
A. Absolute recovery:
Area in plasma / Area in water •
Low (0.3 g/ml)….91.45% •
Med (1.5 g/ml)….87.54%
High (3 g/ml)….86.85%
B. Relative recovery
Replicate analysis (n=6) •
Comparing recovered conc. to the added •
Low (0.3 g/ml)….111,7% •
Med (1.5 g/ml)….97.1%
High (3 g/ml)….100.9%
C. Within day reproducibility
Replicate analysis (n=6) •
Low….CV 4.97% •
Med….CV 5.33%
High….CV 4.69%
D. Between days reproducibility
St. curve (n=6) •
17 days •
CV% ….9.31 •
E. Stability in freezer
Conc. (0.3 and 3 µg /ml) •
14 days •
91.9 - 100 % •
1. Verbal pain score
no pain = 0
mild
=1
moderate = 2
severe = 3
2. VAS
Cp = D / Vd e -Kel.t •
Cp =D ( - k12) / Vc ( -  ) e -t + D ( k21 - •
) / Vc ( - ) e -t
t

AUC 0 = AUC 0 + 1.44 t1/2 Ct •
MRT = AUMC / AUC •
t

AUMC 0 = AUMC 0 + Ct / 2 + tC /  •
cl = K10 Vc •
Vss = Vc (1 + K12 / K21) •
Student t-test •
Wilcoxon rank sum test •
Mann-Whitney U test •
NLREG •
KINETICA •
WINNONLIN •
RSTRIP •
Pkanalyst •
SPSS •
ABOUKIN & ABOUSTAT •
A. One-compartment
Pt.
dg
Kel
T1/2
Vd
Cl
4
keto
0.34
2.04
16.37
5.57
6
keto
1.95
0.35
4.3
8.39
9
Ket + Pet
0.35
1.97
11.85
4.17
10
Ket + Pet
0.46
1.51
16.13
7.48
B. Two-compartment
Pt.


K 10
K 12
K 21
1 (k)
1.82
0.34
0.81
0.59
0.76
2 (k)
0.91
0.06
0.49
0.38
0.10
5 (k)
2.37
0.17
3 (k+p) 0.78
0.0012
7 (k+p) 0.44
0.03
0.43
0.004
0.03
8 (k+p) 2.28
0.20
1.18
0.91
0.39
C. Non-compartment analysis
parameter
Mean ± SD
Keto
Mean ± SD
Keto + Peth
p
sig
Kel
0.37 ± 0.19
0.30 ± 0.1
0.45
NS
T1/2
2.4 ± 1.42
2.48 ± 0.89
0.51
NS
AUCt/AUC
95.93 ± 4.1
88.41 ± 6.14
0.052
NS
MRT
2.1 ± 1.25
2.49 ± 0.48
0.53
NS
Vss
11.33 ± 6.43
12.47 ± 4.64
0.75
NS
Cl
5.41 ± 0.81
5.26 ± 1.64
0.86
NS
D. Non-compartment analysis (all
patients)
parameter
Mean ± SD
Kel
0.34 ± 0.14
T1/2
2.44 ± 1.12
AUCt/AUC
92.17 ± 6.34
MRT
2.3 ± 0.91
Vss
11.90 ± 5.32
Cl
5.34 ± 1.22
E. Comparison between modeldependent & independent estimates of
Clearance
Mean ± SD
P
Without model
5.31 ± 1.24
0.72
With model
5.42 ± 1.63
Ratio
1.00 ± 0.13
F. Comparison with published data
Parameter
Williams etal
B
6
This study
n
Debruyne etal
A
7
age
34 ± 9
42.5
28.3 ± 8.17
Kel
1.19 ± 0.16*
N/A
0.34 ± 0.14
T 1/2
1.79 ± 0.5
4.06 ± 1*
2.44 ± 1.12
AUC
20 ± 3.46
18.5 ± 3.25
19.81 ± 4.81
Vss
9.91 ± 1.7
N/A
11.9 ± 5.32
Cl
5.16 ± 0.9
5.41 ± 0.95
5.34 ± 1.22
10
G. Effect of age on PK parameters
parameter
Mean ± SD
Mean ± SD
p
sig
age
38.33 ± 5.77
24 ± 4.12
0.02
S
wt
82.33 ± 8.5
71.57 ± 12.94
0.08
NS
Kel
0.39 ± 0.02
0.31 ± 0.17
0.13
NS
T1/2
1.77 ± 0.07
2.72 ± 1.25
0.05
NS
G. Effect of age on PK parameters
parameter
Mean ± SD
Gp. 1
Mean ± SD
Gp. 2
p
sig
AUC
15.42 ± 2.51
21.69 ± 4.34
0.01
S
MRT
2.41 ± 0.36
2.25 ± 1.1
0.37
NS
Vss
15.35 ± 3.55
10.43 ± 5.46
0.070
NS
Vss norm.
18.34 ± 6.26
10.01 ± 4.05
0.07
NS
Cl
6.61 ± 1.13
4.79 ±0.82
0.04
S
Cl norm.
7.85 ± 2.15
4.95 ± 1.53
0.06
NS
H. Relationship between ketoprofen Cl &
Creatinine Cl
Jellife: •
Cl cr = 98 - 0.8 ( age - 20 ) / Scr
Cockroft & Gault: •
Cl cr = (140 - age) IBW / 72 Scr
H. Creatinine Cl vs Ketoprofen Cl
Pt (Keto)
Cockroft
CLcr
Jellife
Clcr
Keto
Cl.p
3
96.04
86.90
83.60
7
98.78
77.62
87.50
8
152.29
131.69
54.83
9
88.38
69.62
82
10
163.85
105.03
130.8
Conclusions