Pharmacodynamics - Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that possesses anti-inflammatory, analgesic and antipyretic activity. Its mode of action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition. After absorption of the racemic ibuprofen, the [-]R-enantiomer undergoes interconversion to the [+]S-form. The biological activities of ibuprofen are associated with the [+]S-enantiomer.
Pharmacokinetics - Ibuprofen is a racemic mixture of [-]R-and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~60%) interconverted into the active [+]S species in adults. The degree of interconversion in children is unknown, but is thought to be similar. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. Ibuprofen is well absorbed orally, with less than 1% being excreted in the urine unchanged. It has a biphasic elimination time curve with a plasma half-life of approximately 2 hours. Studies in febrile children have established the dose-proportionality of 5 and 10 mg/kg doses of ibuprofen. Studies in adults have established the dose-proportionality of ibuprofen as a single oral dose from 50 to 600 mg for total drug and up to 1200 mg for free drug.
Absorption - In vivo studies indicate that ibuprofen is well absorbed orally from the suspension formulation, with peak plasma levels usually occurring within 1 to 2 hours (see Table 1).
Table 1 Pharmacokinetic Parameters of Ibuprofen Suspension [Mean values (% coefficient of variation)]
| Dose || 200mg|
| 10mg/kg in Febrile|
| Formulation || Suspension || Suspension |
AUCinf = Area-under-the-curve to infinity
Tmax = Time-to-peak plasma concentration
Cmax = Peak plasma concentration
Cl/F = Clearance divided by fraction at drug absorbed
|Number of Patients||24||18|
Antacids - A bioavailability study in adults has shown that there was no interference with the absorption of ibuprofen when given in conjunction with an antacid containing both aluminum hydroxide and magnesium hydroxide.
H-2 Antagonists – In studies with human volunteers, coadministration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.
Food Effects - Absorption is most rapid when MOTRIN is given under fasting conditions. Administration of MOTRIN Suspension with food affects the rate but not the extent of absorption. When taken with food, Tmax is delayed by approximately 30 to 60 minutes, and peak levels are reduced by approximately 30 to 50%.
Distribution - Ibuprofen, like most drugs of its class, is highly protein bound (>99% bound at 20 μ g/mL). Protein binding is saturable and at concentrations >20 μ g/mL binding is non-linear. Based on oral dosing data there is an age- or fever- related change in volume of distribution for ibuprofen. Febrile children <11 years old have a volume of approximately 0.2 L/kg while adults have a volume of approximately 0.12 L/kg. The clinical significance of these findings is unknown.
Metabolism - Following oral administration, the majority of the dose was recovered in the urine within 24 hours as the hydroxy-(25%) and carboxypropyl-(37%) phenylpropionic acid metabolites. The percentages of free and conjugated ibuprofen found in the urine were approximately 1% and 14%, respectively. The remainder of the drug was found in the stool as both metabolites and unabsorbed drug.
Elimination - Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. It has a biphasic plasma elimination time curve with a half-life of approximately 2.0 hours. There is no difference in the observed terminal elimination rate or half-life between children and adults, however, there is an age-or fever-related change in total clearance. This suggests that the observed change in clearance is due to changes in the volume of distribution of ibuprofen (see Table 1 for Cl/F values).
Clinical Studies - Controlled clinical trials comparing doses of 5 and 10 mg/kg ibuprofen suspension and 10-15 mg/kg of acetaminophen elixir have been conducted in children 6 months to 12 years of age with fever primarily due to viral illnesses. In these studies there were no differences between treatments in fever reduction for the first hour and maximum fever reduction occurred between 2 and 4 hours. Response after 1 hour was dependent on both the level of temperature elevation as well as the treatment. In children with baseline temperatures at or below 102.5°F both ibuprofen doses and acetaminophen were equally effective in their maximum effect. In children with temperatures above 102.5°F, the ibuprofen 10 mg/kg dose was more effective. By 6 hours, children treated with ibuprofen 5mg/kg tended to have recurrence of fever, whereas children treated with ibuprofen 10 mg/kg still had significant fever reduction at 8 hours. In control groups treated with 10 mg/kg acetaminophen, fever reduction resembled that seen in children treated with 5 mg/kg of ibuprofen, with the exception that temperature elevation tended to return 1-2 hours earlier.
In patients with primary dysmenorrhea, ibuprofen has been shown to reduce elevated levels of prostaglandin activity in the menstrual fluid and to reduce testing and active intrauterine pressure, as well as the frequency of uterine contractions. The probable mechanism of action is to inhibit prostaglandin synthesis rather than simply to provide analgesia.