Comparative Bioavailability and Pharmacodynamic Aspects of Cyclobenzaprine and Caffeine in Healthy Subjects and the Effect on Drowsiness Intensity

A specific, fast and sensitive LC–MS/MS assay was d e- veloped for the determination of cyclobenzaprine in hu- man plasma using imipramine as the internal standar d (IS). The limit of quantification was 0.05 ng/mL and the method was linear in the range of 0.05 to 50 ng/mL. The cyclobenzaprine and IS retention times were 2.74±0. 2 min and 2.69±0.2 min, respectively. Method intra-batch precision and accuracy ranged fr om 2.90 to 9.72%, and 91.63 to 107.33%, respectively. Inter- batch precision ranged from 3.37 to 10.27%, while I nter- batch accuracy ranged from 96.13 to 106.10%. The an a- lytical method was applied to evaluate the pharmaco ki- netic and relative bioavailability of two different pharma- ceutical formulations containing cyclobenzaprine, o ne test tablet containing 10 mg of cyclobenzaprine plus 60 mg of caffeine (Miosan ® /cafeine) and the reference Miosan ® con- taining only 10 mg of cyclobenzaprine, manufactured by the same pharmaceutical company. In addition to the phar- macokinetic analysis, a pharmacodinamic evaluation of the drowsiness intensity during the confinement per iods was conducted in order to evaluate the caffeine eff ect. This study evaluated 34 subjects in a randomized, 2-peri od crossover study with 14 days washout period between doses. Based on the 90% confidence interval of the individ ual ratios (test formulation/reference formulation) for C max and AUC inf , it was concluded that the test formulation is bioequivalent to the reference Miosan ® with respect to the rate and extent of absorption of cyclobenzaprine an d that caffeine had no effect on the relative pharmacokine tic pa- rameters. However, based on the Stanford point anal ysis, the combination of Miosan ® with caffeine in the same tab- let formulation significantly decreased the drowsin ess in- tensity observed during the confinement periods.