Pharmacokinetic Study of a New Ibuprofen 600mg plus Codeine 30mg Combination versus Ibuprofen or Codeine Alone in Single Oral Doses in Healthy Volunteers

Abstract

Objective: To compare the bioavailability parameter values of ibuprofen 600mg or codeine 30mg when administered in a new combined solid oral formulation versus each agent administered alone. Design: Non-blind, comparative, crossover, three-way (ibuprofen, codeine, ibuprofen plus codeine) randomised clinical trial. Setting: Phase 1 study unit. Subjects: 24 healthy volunteers of both genders (12 males and 12 females) with the following average characteristics: age 22.6 years; bodyweight 63.2kg; height 171cm; body mass index 21.47 kg/m2. Interventions: During each study period, a single oral dose of one of the formulations was administered, and 13 plasma samples were obtained to determine drug concentrations and calculate pharamcokinetic parameter values. Results: The pharmacokinetic parameter values [mean ± standard deviation, except median for time to maximum plasma concentration (tmax)] calculated for each drug and formulation were as follows: For ibuprofen (combined with codeine) versus ibuprofen alone: area under the concentration-time curve from time zero to infinity (AUC0-∞), 202.06 ± 43.62 vs 204.19 ± 52.79 mg·h/L; maximum plasma concentration (Cmax), 64.93 ± 11.91 vs 57.01 ± 15.47 mg/L; tmax, 1.00 vs 1.50h. The 90% confidence intervals (CI90) of the ratios (%) of logarithmically transformed values were: AUC0-∞ 95.88 to 104.22; Cmax 104.75 to 129.63; the CI90 (Wilcoxon test) of the median difference in tmax was −0.80 to −0.13h. For codeine (combined with ibuprofen) versus codeine alone: AUC0-∞ 417.82 ±115.55 vs 354.36 ±114.43 μg·h/L; Cmax115.12 ± 38.85 vs 89.05 ± 27.09 μg/L; tmax 1.00 vs 1.00h. The CI90 of the ratios (%) of logarithmically transformed values were: AUC0-∞ 111.84 to 126.18; Cmax 116.66 to 139.57; the CI90 (Wilcoxon test) of the median difference in tmax was −0.25 to 0.17h. Conclusions: The rate and extent of ibuprofen release/absorption from both formulations are within bioequivalence limits. The extent of absorption of codeine is slightly greater from the combination form, with a similar rate of release/absorption. The slight differences found are attributable to the galenic formulations. These results confirm the good bioavailability of ibuprofen and codeine from the new formulation, and exclude any impairment of absorption when the drugs are formulated in combination.