Pharmacokinetic evaluation of a new oral sustained release dosage form of tramadol

Aims: To compare the pharmacokinetic profile of a new modified release formulation of tramadol (Tramadol LP 200 mg, SMB Technology, Marche-en-Famenne, Belgium) with that of an immediate release capsule (Topalgic® 50 mg, Grünenthal, Aachen, Germany) after single and multiple dosing and to assess the potential effect of food on its relative bioavailability. Methods: The first study had an open, single-dose, three-treatment, three-period, six-sequence, randomised, crossover design with at least a five-day wash-out. The second study had an open, steady-state, two-treatment, two-period, two-sequence, randomised crossover design with at least a seven-day wash-out. Both studies contained 30 healthy subjects. Both enantiomers of tramadol and O-demethyl-tramadol (the only active metabolite of tramadol) were assayed in the plasma using an LC-MS/MS method. AUC∞, AUCt, Cmax, Tmax, and T1/2 were estimated. Statistical analysis was performed using univariate ANOVA, the Wilcoxon nonparametric method or Friedman's nonparametric ANOVA where appropriate. Results: Tramadol had a significantly lower Cmax and longer Tmax than the conventional formulation. Thus, the mean (± sd) Cmax, of tramadol were 646 ± 192 and 300 ± 94 ng ml-1 for Topalgic® 4 x 50mg and Tramadol LP 200 mg, respectively (95% confidence interval on the difference expressed as a percentage 42-51). AUC of tramadol from both formulations was comparable (similar AUC∞ and AUCt). Thus, the mean AUC∞ of (+/-)tramadol obtained after multiple dosing were 4611 ± 1944 and 5105 ± 2101 ngh ml-1 after Topalgic® 4 x 50mg and Tramadol LP 200 mg, respectively (95%Cl 102-123%). We also demonstrate that the pharmacokinetics of the drug are not influenced by the intake of food. Thus, the mean AUC∞ of (+/-) tramadol were 5444 ± 1637 and 5169 ± 1580 ngh ml-1 after Tramadol LP 200 mg given in the fasting and fed states, respectively (95%Cl = 88-103%). Conclusions: The new sustained release form of tramadol exhibits adequate properties for once a day administration. Furthermore, its pharmacokinetic profile is not affected by the intake of food.SCOPUS: ar.jFLWIN