Phase I Pharmacokinetic Study of Fixed-Dose Combinations of Ibuprofen and Acetaminophen in Healthy Adult and Adolescent Populations

Abstract

Introduction A fixed-dose combination (FDC) of ibuprofen and acetaminophen has been developed that provides greater analgesic efficacy than either agent alone at the same doses without increasing the risk for adverse events. Methods We report three clinical phase I studies designed to assess the pharmacokinetics (PK) of the FDC of ibuprofen/ acetaminophen 250/500 mg (administered as two tablets of ibuprofen 125 mg/acetaminophen 250 mg) in comparison with its individual components administered alone or together, and to determine the effect of food on the PK of the FDC. Two studies in healthy adults aged 18-55 years used a crossover design in which subjects received a single dose of each treatment with a 2-day washout period between each. In the third study, the bioavailability of ibuprofen and acetaminophen from a single oral dose of the FDC was assessed in healthy adolescents aged 12-17 years, inclusive. Results A total of 35 and 46 subjects were enrolled in the two adult studies, respectively, and 21 were enrolled in the adolescent study. Ibuprofen and acetaminophen in the FDC were bioequivalent to the monocomponents administered alone or together. With food, the maximum concentration (C max ) for ibuprofen and acetaminophen from the FDC was reduced by 36% and 37%, respectively, and time to C max (i.e. t max ) was delayed. Overall drug exposure to ibuprofen or acetaminophen in the fed versus fasted states was similar. In adolescents, overall exposure to acetaminophen and ibuprofen was comparable with that in adults, with a slightly higher overall exposure to ibuprofen. Exposure to acetaminophen and ibuprofen in adolescents aged 12-14 years was slightly higher versus those aged 15-17 years. Adverse events were similar across all treatment groups. Conclusions The FDC of ibuprofen/acetaminophen 250/500 mg has a PK profile similar to its monocomponent constituents when administered separately or coadministered, indicating no drug-drug interactions and no formulation effects. Similar to previous findings for the individual components, the rates of absorption of ibuprofen and acetaminophen from the FDC were slightly delayed in the presence of food. Overall, adolescents had similar exposures to acetaminophen and ibuprofen as adults, while younger adolescents had slightly greater exposure than older adolescents, probably due to their smaller body size. The FDC was generally well tolerated.

Evaluation of Fixed-Dose Combinations of Ibuprofen and Acetaminophen in the Treatment of Postsurgical Dental Pain: A Pilot, Dose-Ranging, Randomized Study

“…However, FDC IBU/APAP 200 mg/500 mg and FDC IBU/APAP 300 mg/500 mg were significant versus ibuprofen 400 mg for SPRID [4] 0-2 (p < 0.05). Similar patterns were seen for time-weighted SPID [4] and SPID [11] scores over the same time intervals (data not shown).…”

“…Ibuprofen and acetaminophen do not share metabolic pathways, which diminishes the likelihood of drug–drug interactions [ 8 , 9 ]. Pharmacokinetic studies have demonstrated a lack of drug–drug interactions between ibuprofen and acetaminophen [ 6 , 10 , 11 ]. Ibuprofen and acetaminophen also have different side-effect profiles.…”

Safety and tolerability of fixed-dose combinations of ibuprofen and acetaminophen: pooled analysis of phase 1–3 clinical trials

“…Five of the trials enrolled otherwise healthy adults; two trials included participants that were healthy adolescents. In all, the trials comprised three phase 1 PK trials (2 single-dose trials in adults; 1 single-dose trial in adolescents) [21], 3 dental pain model efficacy trials (a phase 2 single-dose proof-of-concept [26]), a phase 3 single-dose, and a phase 3 multiple-dose trial [20], and 1 single-dose phase 3 trial using an endotoxin-induced fever model. Details of the individual studies included in this pooled safety analysis are provided in Table 1.…”

“…Details of the individual studies included in this pooled safety analysis are provided in Table 1. In all studies, patients were monitored for AEs throughout the study and AEs were reported through 14 days after administration of the last dose of study drug regardless of causality [21,26]. In the dental pain model studies, patients were permitted to take immediate-release tramadol or codeine phosphate at any time during the study as rescue medication, but were encouraged to wait at least 1 hour [26] after study medication administration before doing so.…”

“…In dental pain models, treatment with this FDC produced greater analgesia than the same dose of each individual monocomponent alone [20]. In addition, PK trials have further demonstrated that single or multiple doses of the FDC do not result in increased drug exposure relative to standard OTC monocomponent dosing [21]. Previous investigations of various FDCs of IBU and APAP have demonstrated that the combination is effective in management of acute pain and that it has a safety profile similar to those of corresponding doses of the individual components [3,[22][23][24][25].…”