Ketoprofen is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties.
The anti-inflammatory, analgesic and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro test systems. In anti-inflammatory models ketoprofen has been shown to have inhibitory effects on prostaglandin and leukotriene synthesis, to have antibradykinin activity, as well as to have lysosomal membrane-stabilizing action. However, its mode of action, like that of other non-steroidal anti-inflammatory drugs, is not fully understood.
Pharmacodynamics — Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The enantiomers have similar concentration time curves and do not appear to interact with one another.
An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain study with Ketoprofen Capsules, USP. The effect-site rate constant (k e0) was estimated to be 0.9 hour (95% confidence limits: 0 to 2.1), and the concentration (C e50) of ketoprofen that produced one-half the maximum PID (pain intensity difference) was 0.3 mcg/mL (95% confidence limits: 0.1 to 0.5). Thirty-three (33) to 68% of patients had an onset of action (as measured by reporting some pain relief) within 30 minutes following a single oral dose in postoperative pain and dysmenorrhea studies. Pain relief (as measured by remedication) persisted for up to 6 hours in 26 to 72% of patients in these studies.
General — The systemic availability (FS) when the oral formulation is compared with IV administration is approximately 90% in humans. For 75 to 200 mg single doses, the area under the curve has been shown to be dose proportional.
Ketoprofen is > 99% bound to plasma proteins, mainly to albumin.
Absorption — Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0.5 to 2 hours.
When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed.
Food intake reduces C maxby approximately one-half and increases the mean time to peak concentration (t max) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian changes in the absorption process.
Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen from Ketoprofen capsules, USP.
Multiple Dosing — Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with Ketorpofen Capsules, USP. In studies with healthy male volunteers, trough levels at 24 hours following administration of Ketoprofen Capsules, USP 50 mg capsules QID for 12 hours were 0.07 mg/L and 0.13 mg/L at 24 hours following administration of Ketoprofen Capsules, USP 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of Ketoprofen Capsules, USP is minimal.
The figure below shows a reduction in peak height and area after the second 50 mg dose. This is probably due to a combination of food effects, circadian effects, and plasma sampling times. It is unclear to what extent each factor contributes to the loss of peak height and area.
The shaded area represents ± 1 standard deviation (S.D.) around the mean for immediate-release ketoprofen capsules.
KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING Ketoprofen Capsules, USP 50 MG EVERY 4 HOURS FOR 16 HOURS
Metabolism — The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug, and this may be important in persons with renal insufficiency, whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent drug (see Special Populations, Renally Impaired). The conjugates are reported to appear only in trace amounts in plasma in healthy adults, but are higher in elderly subjects-presumably because of reduced renal clearance. It has been demonstrated that in elderly subjects following multiple doses (50 mg every 6 h), the ratio of conjugated to parent ketoprofen AUC was 30% and 3%, respectively, for the S & R enantiomers.
There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug-metabolizing enzymes.
Elimination — The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vd of 0.1 L/kg after IV administration. The elimination half-life of ketoprofen has been reported to be 2.05 ± 0.58 h (Mean ± S.D.) following IV administration from 2 to 4 hours following administration of ketoprofen capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus t1/2 relative to an IV dose appears prolonged.
In a 24 hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine, primarily as the glucuronide metabolite.
Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been measured to confirm this.
