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

Abstract

AimsTo 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. MethodsThe 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 • , AUC t , C max , T max , and T 1/2 were estimated. Statistical analysis was performed using univariate ANOVA , the Wilcoxon nonparametric method or Friedman's nonparametric ANOVA where appropriate. ResultsTramadol had a significantly lower C max and longer Tmax than the conventional formulation. Thus, the mean ( ± sd) C max of tramadol were 646 ± 192 and 300 ± 94 ng ml -1 for Topalgic® 4 ¥ 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 AUC t ). Thus, the mean AUC • of ( + /-)tramadol obtained after multiple dosing were 4611 ± 1944 and 5105 ± 2101 ngh ml -1 after Topalgic® 4 ¥ 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 • 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%). ConclusionsThe new sustained release form of tramadol exhibits adequate proper ties for once a day administration. Furthermore, its pharmacokinetic profile is not affected by the intake of food. Tramadol sustained release pharmacokineticsBr J Clin Pharmacol 57 :3 271

Stereospecific high-performance liquid chromatographic analysis of tramadol and its O-demethylated (M1) and N,O-demethylated (M5) metabolites in human plasma

“…5) are very similar to those reported before using an identical dosage regimen of immediate release racemic T [25]. Our maximum and minimum concentrations of 190 and 96.7 ng/ml for (+)-T are very close to the reported average of 190 and 111 ng/ml, respectively.…”

Pharmacokinetic and urine profile of tramadol and its major metabolites following oral immediate release capsules administration in dogs

“…A target plasma concentration of tramadol of 100 ng/ ml was clinically effective in the treatment of mild to moderate pain in humans (Malonne et al 2004). In the current study, the plasma concentrations of tramadol were very close to this value, from 0.25 up to 5 h following dosing, while M1 from 0.25 up to 1 h. Regardless, in order to clarify the effectiveness of tramadol in the dog, further studies are necessary to assess the real minimum effective concentration and the analgesic effect.…”

Pharmacokinetics and dose proportionality of three Tramadol Contramid® OAD tablet strengths

“…Although the overall extent of tramadol exposure (based on their respective AUCs), is generally similar among equipotent currently marketed modified-release formulations, differences in the concentration-time profiles of these products are evident, presumably reflecting differences in the rate of drug release from the dosage forms [19][20][21]. For example, following administration of Tramadol LP and Tramadol ER, due to a lag time in drug release, plasma tramadol levels associated with analgesia were not attained until 4-6 h post-dose and the median T max does not occur until 510 h post-dose [20,21]. At steady state, in the first few hours following administration of a formulation with a lag time, plasma drug levels would be expected to decline [19].…”

“…Blood samples (5 ml) were collected into lithium heparinized glass tubes (Venoject 1 ) via cannula or direct venipuncture prior to dosing and at 1, 2, 3, 4, 5,6,8,10,12,16,20,24,30,36 and 48 h postdose. Blood samples were centrifuged at 48C at 4000 rpm for 10 min and the resulting plasma was separated into duplicate polystyrene crystal tubes and stored frozen between À208C and À308C pending analysis.…”