The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol

Abstract

Background: Ibuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet.

Methods: Both studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study.

Results: Pharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 microg x mL(-1) and 16.81 microg x mL(-1), respectively, for ibuprofen from the combination, compared with 0.58 microg x mL(-1) and 9.00 microg x mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 microg x mL(-1) and 14.54 microg x mL(-, respectively, for the combination compared with 0.33 microg x mL(-1) and 9.19 microg x mL(-1), respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily.

Conclusions: Administration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.

Figures

Figure 1

Mean plasma ibuprofen concentration time curves after administration of ibuprofen monotherapy and ibuprofen-paracetamol fixed-dose combination tablets (Study 1).

Figure 2

Mean plasma paracetamol concentration time curves after administration of paracetamol monotherapy and ibuprofen-paracetamol fixed-dose combination tablets (Study 1).

Figure 3

Mean plasma ibuprofen and paracetamol concentration time curves after administration of ibuprofen-paracetamol fixed-dose combination tablets in the fed and fasted states (Study 1).

Figure 4

Mean plasma ibuprofen and paracetamol concentrations time curves following administration of the first dose in subjects allocated to receive twice or three times daily dosing with ibuprofen-paracetamol fixed-dose combination tablets (Study 2; Day 2).

Figure 5

Comparison of mean plasma ibuprofen and paracetamol concentration time curves after administration of the first dose (on Day 2) and following three days of treatment (Day 4) with ibuprofen-paracetamol fixed-dose combination tablets at twice daily dosing.

Figure 6

Comparison of mean plasma ibuprofen and paracetamol concentration time curves after administration of the first dose (on Day 2) and following three days of treatment (Day 4) with ibuprofen-paracetamol fixed-dose combination tablets at three times days daily dosing.