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

Abstract

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 infinity, 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 infinity and AUCt). Thus, the mean AUC infinity 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%CI 102-123%). We also demonstrate that the pharmacokinetics of the drug are not influenced by the intake of food. Thus, the mean AUC infinity 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%CI = 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.

Figure 1

Mean (±sd) plasma concentration-time profiles for (+)– tramadol after a single oral administration of an immediate release form (Topalgic) in the fasting state; or a sustained release form (Tramadol LP) in the fed and fasting states. NF = after fasting, F = after a fatty meal. Topalgic NF (♦), tramadol LP NF (▪) and tramadol LP F (▴)

Figure 2

Mean (± sd) plasma concentration-time profiles of (+)–O-demethyltramadol after a single oral administration of an immediate release form (Topalgic) in the fasting state; or a sustained release form (Tramadol LP) in the fed and fasting states. NF = after fasting, F = after a fatty meal. Topalgic NF (♦), tramadol LP NF (▪) and tramadol LP F (▴)

Figure 3

Mean (± sd) plasma concentration-time profiles of (+)– tramadol after repeated oral administration of an immediate release form (Topalgic) in the fasting state; or a sustained release form (Tramadol LP) in the fasting state. Topalgic 50 mg average (♦) and Tramadol LP 200 mg average (▪)

Figure 4

Mean (± sd) plasma concentration-time profiles of (+)–O-demethyltramadol after repeated oral administration of an immediate release form (Topalgic) in the fasting state; or a sustained release form (Tramadol LP) in the fasting state. Topalgic 50 mg average (♦) and Tramadol LP 200 mg average (▪)

Figure 5

Mean (± sd) plasma concentration profiles for the sum of the enantiomers of tramadol after 7 days dosing with the immediate release form (Topalgic, 50 mg 4 times daily) or the sustained release form (Tramadol, 200 mg once daily). Topalgic trama 1 + 2 (•), trama LP trama 1 + 2 (▪) and therapeutic threshold (100) (—)