PHARMACOKINETICS OF KETOPROFEN

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A COMPARATIVE STUDY IN PRESENCE AND ABSENCE OF
PETHIDINE AFTER SURGERY
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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.
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Objectives
4. Effect of age on PK of ketoprofen. 5.
Assessment of pain relief in ketoprofen compared
to ketoprofen plus Pethidine.
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Introduction

• What is Ketoprofen ?
• What is Pethidine ?
• Uses of Ketoprofen
• Interactions

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Introduction
Mode of action
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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

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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

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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

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Introduction
Literature Review

• Ketoprofen associated with faster recovery from
  anaesthesia required less post-operative
  analgesia compared to pethidine after nasal
  surgery.
• Elhakeem etal
  1991

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Methodology
A. Study design
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1. Demographic data
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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
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Methodology
B. Ketoprofen Assay (HPLC)
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1. Chromatographic conditions

• Mobile phase 50 methanol, 50 deionized water,
  2 ml glacial aaPH5
• Flow rate 2 ml / min
• ? max 254 nm
• Attenuation 0.05

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2. Apparatus

• Pump model 501
• Injector model 717
• Integrator model 746
• Detector model 484
• C18 cartidge (15 cm ? Bonda pack)

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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

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• B. Relative recovery
• Replicate analysis (n6)
• 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

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• C. Within day reproducibility
• Replicate analysis (n6)
• Low.CV 4.97
• Med.CV 5.33
• High.CV 4.69

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• D. Between days reproducibility
• St. curve (n6)
• 17 days
• CV .9.31

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• E. Stability in freezer
• Conc. (0.3 and 3 µg /ml)
• 14 days
• 91.9 - 100

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C. Assessment of Pain
1. Verbal pain score no pain 0
mild 1 moderate 2 severe
3 2. VAS
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D. Data analysis

• Cp D / Vd e -Kel.t
• Cp D (? - k12) / Vc (? - ? ) e -?t D ( k21 -
  ?) / Vc (? - ?) e -?t
• AUC ??0 AUC t?0 1.44 t1/2 Ct
• MRT AUMC / AUC
• AUMC ??0 AUMC t?0 Ct / ?2 tC / ?
• cl K10 Vc
• Vss Vc (1 K12 / K21)

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E. Statistical Analysis

• Student t-test
• Wilcoxon rank sum test
• Mann-Whitney U test

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F. Computer Software

• NLREG
• KINETICA
• WINNONLIN
• RSTRIP
• Pkanalyst
• SPSS
• ABOUKIN ABOUSTAT

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A. One-compartment
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B. Two-compartment
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C. Non-compartment analysis
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D. Non-compartment analysis (all patients)
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E. Comparison between model- dependent
independent estimates of Clearance
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F. Comparison with published data
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G. Effect of age on PK parameters
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G. Effect of age on PK parameters
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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

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H. Creatinine Cl vs Ketoprofen Cl
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Conclusions