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∞, 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 × 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 × 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%).
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.
Introduction
Tramadol HCl (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is a centrally acting analgesic. Unlike others members of this pharmacological class such as hydrocodone, oxycodone or codeine, this drug at therapeutic doses possesses a dual mechanism of action [1]. Tramadol displays a weak affinity for the µ- and δ-opioid receptors and an even weaker affinity for the κ-subtype. It also interferes with the neuronal release and reuptake of serotonin (5HT) and noradrenaline (NA) in the descending inhibitory pathways [2–4]. Tramadol is a racemic mixture of two pharmacologically active enantiomers. These trigger analgesia in a complementary and synergistic manner and exhibit partial antagonism on physiological functions such as colonic motility in rodents and humans [5–7]. The (+) enantiomer inhibits, weakly but preferentially, the reuptake of 5HT and acts on the µ-opioid receptor, whereas the (–) enantiomer inhibits preferentially NA reuptake. O-demethyltramadol, its only active metabolite, shows a slightly greater affinity for the µ-opioid receptor. However, the metabolite appears to contribute minimally to analgesia, at least after a single administration of the drug [8]. This atypical analgesic profile of tramadol has led to its misclassification as a pure analgesic like nefopam or as a classical opiate, which does not reflect entirely its mechanisms of action.
Tramadol is almost completely absorbed when given orally, and has an apparent elimination half-life of 6 h in humans. Its bioavailability of 70% after a single administration can be attributed entirely to first pass metabolism. After multiple dosing the bioavailability rises to almost 100%. Twenty per cent of the drug is bound to plasma proteins. Approximately 90% of the administered dose is recovered in urine either unchanged (30%) or as metabolites (60%) and the remainder is eliminated in the faeces [9]. At least 11 tramadol metabolites have been identified. Of these, there was only one active (O-demethyltramadol, M1) with pharmacological activity. Tramadol elimination is described by a two-compartment pharmacokinetic model, with a reported elimination half-time of 5.1 h after oral administration. The half-life of O-demethyltramadol is somewhat longer (9 h). As tramadol is extensively metabolized in the liver and is eliminated primarily by renal excretion, an increase in the apparent elimination half-life occurs in patients with renal or hepatic failures [1, 10]. Epidemiological studies from Germany, the country where tramadol was first launched on the market (in 1977), have demonstrated a very low potential for addiction, minimal tolerance and limited cross-tolerance with morphine [11–13].
The pharmacokinetic and safety profiles of tramadol have stimulated the development of slow-release formulations, some of which have already been marketed in various countries [14]. An oral once a day, sustained release formulation of tramadol has advantages over immediate release preparations since it decreases peak plasma concentrations, thus minimizing acute adverse effects of the drug. It can also improve patient compliance by simplifying the dosing regimens.
A new once-a-day formulation of tramadol (Tramadol LP) has been developed in three different dosage strengths, namely 100 mg, 150 mg and 200 mg, each exhibiting in vitro a stable and sustained release of drug for at least 24 h. The formulation is a hard gelatine capsule containing coated beads of tramadol. Multiparticulate formulations have several significant advantages such as less intra and intersubject variability in pharmacokinetics than their monolithic counterparts.
The aim of the present study was to compare the pharmacokinetic profile in healthy subjects of an immediate release formulation of tramadol with that of Tramadol LP slow release after single and multiple dose administration. A further aim of the study was to evaluate whether the concomitant food intake has an influence on the relative bioavailability of this new formulation.
Materials and methods
Study population and design
Both studies had an open, randomized, cross-over design. The subjects were 30 healthy caucasians, who were equally balanced sex, were aged from 18 to 50 years, were non smokers or smoked less than 10 cigarettes a day. None of the female subjects was pregnant or breastfeeding.
In the first study the pharmacokinetic profile of the immediate release tramadol (Topalgic®; 4 × 50 mg capsules) was compared with that of sustained release tramadol (Tramadol LP 200 mg, Laboratoires SMB SA) both given in the fasted state. Tramadol LP (200 mg) was also administered on a different occasion and after a fatty meal. There was a wash-out period of five days between each phase of the study.
In the second study the pharmacokinetics of immediate release tramadol (50 mg given every 6 h) were compared to those of sustained release tramadol (200 mg given once a day) in the fasting state. The total duration of this study was 23 days, comprising seven days on the first treatment followed by a wash-out period of seven days, and then seven days on the second treatment plus two days of sampling.
Both studies were conducted in accordance with the ethical principles of the Declaration of Helsinki, in compliance with the approved protocol, Good Clinical Practices (GCP) and applicable regulatory requirements. The study protocols were approved by an independent ethics committee in accordance with ICH regulations (First study: Ethics Committee, CHU, Faculty of Medicine, Liège, Belgium. Second study: Independent Ethics Committee, CCPPRB, Boucicaut Hospital, Paris, France). Informed consent was given by each subject in writing prior to the start of the study. The subjects underwent physical and laboratory examination and were judged healthy prior to entering the study. The subjects fasted for at least 10 h (food) and 3 h (drink) before dosing. For the study of the effects of food, a standardized high-fat breakfast was eaten before dosing, the content of which was bread with butter, one fried egg, two slices of bacon, one serving of fresh brown potatoes, 180 ml of orange juice and 240 ml of whole milk. No intake of alcohol, caffeine and xanthine containing foods or drink, and no drugs or foodstuffs that may interact with tramadol metabolism were allowed during the study (for example, cabbage, grapefruit or pineapple juice).
Blood sampling
Heparinized blood samples were taken at the following times: Single dose study: −0.50 (prior to administration), 0.25, 0.50, 1.00, 1.50, 2.00, 4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 20.00, 24.00, 28.00 and 36.00 h post administration. Repeated dose study: −0.50, 0.00, 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 6.50, 7.00, 7.50, 8.00, 9.00, 10.00, 11.00, 12.00, 12.50, 13.00, 13.50, 14.00, 15.00, 16.00, 17.00, 18.00, 18.50, 19.00, 19.50, 20.00, 21.00, 22.00, 24.00, 28.00, and 36.00 h after the first drug administration (immediate release capsule) and −0.50 (prior to administration), 1.00, 1.50, 2.00, 4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 28.00, and 36.00 h after the first drug administration (sustained release capsule). For both studies, an indwelling catheter was inserted into the forearm vein on the two days of dosing.
Sample preparation
The blood samples were shaken gently and centrifuged for 20 min After appropriate labelling, the plasma samples were stored deep frozen (−80 ± 5 °C) in an upright position in polypropylene tubes pending analysis.
Determination of tramadol and O-demethyltramadol
The enantiomers of tramadol and O-demethyltramadol in human plasma were measured as described previously [22]. Briefly, the separation of the enantiomers was effected by using a mobile phase composed of isohexane-ethanol-diethylamine (97 : 3 : 0.1 v/v) and a chiral column (Chiralpak AD CSP). Analysis was by on-line LC-MS/MS using atmospheric pressure chemical ionization. The limit of quantification was 0.15 and 0.17 ng ml−1 for (+)-tramadol and (–)-tramadol, respectively, and 0.29 and 0.33 ng ml−1 for (+)-O-demethyltramadol and (–)-O-demethyltramadol, respectively. The coefficients of variation (n = 6) were between 1.9 and 5.7% for tramadol enantiomers and 2.2–5.6% for O-demethyltramadol enantiomers.
Statistical and pharmacokinetic evaluation
Cmax, the highest observed plasma concentration; Cmin, the lowest observed plasma concentration (at steady-state) and Tmax, the time required to reach Cmax, were obtained from the individual plasma concentration/time curves.
Half-life (t1/2) was calculated from the slope of the logarithm of concentration vs time profile. Area under the concentration/time curve (AUCt) to the last measured concentration was calculated by the linear trapezoidal rule. AUC∞ was calculated from the equation AUC∞= AUCt+ Ct/Ke. The Fluctuation in plasma concentration was calculated from the equation Fluctuation = 100 × (Cmax – Cmin)/Cmin. The attainment of steady-state was confirmed for both tramadol and O-demethyltramadol after multiple dosing.
In both studies, continuous variables (AUC∞, AUCt, Cmax, T1/2, Cmin, Fluctuation) were compared using anova (analysis of variance) adapted to cross-over designs [23]. For Tmax, the Wilcoxon nonparametric test was used. Differences were considered significant if the associated probability level was lower than 0.05. The two formulations were deemed to be bioequivalent if the confidence limits for the ratio of log of AUCt were included in the 80–125% range of acceptance, assuming an additive (multiplicative) model [24, 25]. The confidence limits were calculated according to the method of Shuirman, as adapted by Steinijans et al.[26]. Statistics were performed on log transformed continuous variables.
Results
In the single dose study two subjects did not complete the protocol, and one of these was replaced by a reserve volunteer. Thus, 29 subjects completed the study. Adverse events (headache, dizziness, drowsiness and nausea) were mild or moderate in severity. The number of adverse events was similar during both treatments (data not shown). Figures 1 and 2 show the mean plasma concentration-time profile for (+)-tramadol and (+)-O-demethyltramadol following administration of immediate or sustained release tramadol. The pharmacokinetic profile obtained for the other enantiomers of tramadol and O-demethyltramadol, respectively, are similar (data not shown).
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 (▴)
The pharmacokinetic parameters are summarized in Tables 1 and 2. As expected, sustained release tramadol exhibited a significantly lower Cmax and longer Tmax compared to the immediate release form. However, total systemic exposure to the drug and metabolite enantiomers was similar for both products for both formulations for both AUCt and AUC∞. Food did not significantly modify any of the pharmacokinetic parameters assessed for the sustained release dosage form. Inter-subject variability in the pharmacokinetics of tramadol and metabolite was similar for both formulations.
Table 1.
Calculated pharmacokinetic parameters for tramadol from the food/non food study results. All values are mean ± standard deviation excepted for Tmax, where median (min-max) are listed
| Parameter | Topalgic® 50 mg (4 caps/fasting) (+)-tramadol | Tramadol LP 200 mg (1 caps/fasting) (+)-tramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 5596 ± 0.51916 | 5444 ± 0.51637 | 91–107 |
| AUCT (ng.h/l) | 5483 ± 0.51841 | 4884 ± 0.51326 | 84–98 |
| Cmax (ng/l) | 646 ± 0.5192 | 300 ± 0.5 94 | 42–51 |
| Tmax (h) | 1.3 (1.0–6.0) | 10.0 (6.0–12.0) | – |
| T1/2 (h) | 5.8 ± 0.5 1.1 | 8.8 ± 0.5 2.6 | 136–161 |
| Parameter | Tramadol LP 200 mg (1caps/fasting) (+)-tramadol | Tramadol LP 200 mg (1 caps/fed) (+)-tramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 5444 ± 0.51637 | 5169 ± 0.51580 | 88–103 |
| AUCT (ng.h/l) | 4884 ± 0.51326 | 4692 ± 0.51319 | 89–104 |
| Cmax (ng/l) | 300 ± 0.5 94 | 283 ± 0.5 72 | 87–105 |
| Tmax (h) | 10.0 (6.0–12.0) | 10.0 (8.0–12.0) | – |
| T1/2 (h) | 8.8 ± 0.5 2.6 | 8.3 ± 0.5 1.8 | 88–104 |
| Parameter | Topalgic® 50 mg (4 caps/fasting) (–)-tramadol | Tramadol LP 200 mg (1 caps/fasting) (–)-tramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 4455 ± 0.51562 | 4286 ± 0.51228 | 91–107 |
| AUCT (ng.h/l) | 4405 ± 0.51533 | 3954 ± 0.51081 | 85–100 |
| Cmax (ng/l) | 580 ± 0.5183 | 255 ± 0.5 84 | 40–49 |
| Tmax (h) | 1.3 (1.0–6.0) | 10.0 (6.0–12.0) | – |
| T1/2 (h) | 5.2 ± 0.5 0.8 | 7.8 ± 0.5 2.0 | 135–161 |
| Parameter | Tramadol LP 200 mg (1 caps/fasting) (–)-tramadol | Tramadol LP 200 mg (1 caps/fed) (–)-tramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 4286 ± 0.51228 | 4084 ± 0.51157 | 87–104 |
| AUCT (ng.h/l) | 3954 ± 0.51081 | 3790 ± 0.51038 | 90–102 |
| Cmax (ng/l) | 255 ± 0.5 84 | 241 ± 0.5 65 | 86–106 |
| Tmax (h) | 10.0 (6.0–12.0) | 10.0 (8.0–12.0) | – |
| T1/2 (h) | 7.8 ± 0.5 2.0 | 7.7 ± 0.5 1.5 | 91–108 |
Table 2.
Calculated pharmacokinetic parameters for O-demethyl-tramadol from the food/non food study results
| Parameter | Topalgic®50 mg (4 caps/fasting) (+)-O-demethyltramadol | Tramadol LP 200 mg (1 caps/fasting) (+)-O-demethyltramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 1459 ± 0.5521 | 1464 ± 0.5492 | 93–112 |
| AUCT (ng.h/l) | 1417 ± 0.5510 | 1290 ± 0.5436 | 85–101 |
| Cmax (ng/l) | 127 ± 0.5 56 | 71 ± 0.5 27 | 53–65 |
| Tmax (h) | 2.0 (1.0–6.0) | 12.0 (6.0–20.0) | – |
| T1/2 (h) | 6.9 ± 0.5 1.5 | 9.7 ± 0.5 2.6 | 129–151 |
| Parameter | Tramadol LP 200 mg (1 caps/fasting) (+)-O-demethyltramadol | Tramadol LP 200 mg (1 caps/fed) (+)-O-demethyltramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 1464 ± 0.5492 | 1434 ± 0.5504 | 89–106 |
| AUCT (ng.h/l) | 1290 ± 0.5436 | 1248 ± 0.5459 | 87–104 |
| Cmax (ng/l) | 71 ± 0.5 27 | 71 ± 0.5 28 | 88–110 |
| Tmax (h) | 12.0 (6.0–20.0) | 12.0 (8.0–16.0) | – |
| T1/2 (h) | 9.7 ± 0.5 2.6 | 10.6 ± 0.5 3.1 | 100–117 |
| Parameter | Topalgic® 50 mg (4 caps/fasting) (–)-O-demethyltramadol | Tramadol LP 200 mg (1 caps/fasting) (–)-O-demethyltramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 1572 ± 0.5403 | 1511 ± 0.5400 | 89–103 |
| AUCT (ng.h/l) | 1542 ± 0.5397 | 1365 ± 0.5352 | 83–95 |
| Cmax (ng/l) | 164 ± 0.5 52 | 77 ± 0.5 23 | 43–52 |
| Tmax (h) | 1.3 (1.0–8.0) | 10.0 (6.0–20.0) | – |
| T1/2 (h) | 6.1 ± 0.5 0.9 | 8.6 ± 0.5 2.1 | 127–149 |
| Parameter | Tramadol LP 200 mg (1 caps/fasting) (–)-O-demethyltramadol | Tramadol LP 200 mg (1 caps/fed) (–)-O-demethyltramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/l) | 1511 ± 0.5400 | 1476 ± 0.5387 | 91–105 |
| AUCT (ng.h/l) | 1365 ± 0.5352 | 1326 ± 0.5345 | 90–104 |
| Cmax (ng/l) | 77 ± 0.5 23 | 78 ± 0.5 22 | 92–111 |
| Tmax (h) | 10.0 (6.0–20.0) | 10.0 (8.0–16.0) | – |
| T1/2 (h) | 8.6 ± 0.5 2.1 | 9.0 ± 0.5 1.8 | 98–115 |
In the repeated dose study, only a few adverse events were recorded, most of them (headache, dizziness, tiredness, and nausea) were mild to moderate. Figures 3 and 4 show the mean plasma concentration-time profiles for (+)-tramadol and (+)-O-demethyltramadol enantiomers following immediate or sustained release tramadol administration, and the pharmacokinetic parameters are summarized in Tables 3 and 4.
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 (▪)
Table 3.
Calculated pharmacokinetic parameters for O-demethyl-tramadol after repeated dosing for seven days
| PARAMETER (units) | Topalgic®50 mg (mean ± 0.5 st. dev.) (+)-tramadol | Tramadol LP 200 mg (mean ± 0.5 st. dev.) (+)-tramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/ml) | 4611 ± 0.51944 | 5105 ± 0.52100 | 102–123 |
| AUC24 h (ng.h/ml) | 3429 ± 0.51260 | 3763 ± 0.51275 | 104–119 |
| Cmax (ng/ml) | 190 ± 0.5 56 | 239 ± 0.5 81 | 115–135 |
| Cmin (ng/ml) | 111 ± 0.5 48 | 81 ± 0.5 36 | 64–85 |
| Tmax (h) | 1.8 (0.5–4.0) | 10.0 (6.0–16.0) | – |
| T1/2 (h) | 6.5 ± 0.5 1.7 | 9.7 ± 0.5 3.0 | 133–167 |
| Fluctuation | 57 ± 0.5 10 | 66 ± 0.5 9 | 207–338 |
| PARAMETER (units) | Topalgic® 50 mg (mean ± 0.5 st. dev.) (–)-tramadol | Tramadol LP 200 mg (mean ± 0.5 st. dev.) (–)-tramadol | |
|---|---|---|---|
| AUC∞ (ng.h/ml) | 3530 ± 0.51580 | 3909 ± 0.51698 | 103–122 |
| AUC24 h (ng.h/ml) | 2719 ± 0.51093 | 3005 ± 0.51120 | 105–120 |
| Cmax (ng/ml) | 157 ± 0.5 51 | 199 ± 0.5 75 | 116–134 |
| Cmin (ng/ml) | 86 ± 0.5 42 | 62 ± 0.5 30 | 62–83 |
| Tmax (h) | 1.8 (0.5–4.0) | 10.0 (4.0–16.0) | – |
| T1/2 (h) | 5.6 ± 0.5 1.2 | 8.6 ± 0.5 2.4 | 138–167 |
| Fluctuation | 60 ± 0.5 11 | 69 ± 0.5 9 | 207–336 |
Table 4.
Calculated pharmacokinetic parameters for O-demethyl-tramadol after repeated dosing for seven days
| PARAMETER (units) | Topalgic®50 mg (mean±0.5 st. dev.) (+)-O-demethyltramadol | Tramadol LP 200 mg (mean±0.5 st. dev.) (+)-O-demethyltramadol | 95% CI Expressed as a percentage of the ratio of the values from the two formulations |
|---|---|---|---|
| AUC∞ (ng.h/ml) | 938 ± 0.5402 | 1044 ± 0.5527 | 98–120 |
| AUC24 h (ng.h/ml) | 644 ± 0.5231 | 704.12 ± 0.5327.09 | 97–116 |
| Cmax (ng/ml) | 36 ± 0.5 13 | 42.00 ± 0.5 18.40 | 104–128 |
| Cmin (ng/ml) | 21 ± 0.5 10 | 16.71 ± 0.5 10.41 | 62–88 |
| Tmax (h) | 1.5 (0.5–6.0) | 10.00 (6.00–16.00) | – |
| T1/2 (h) | 8.4 ± 0.5 1.8 | 11.7 ± 0.5 3.1 | 123–157 |
| Fluctuation | 57 ± 0.5 13 | 63 ± 0.5 11 | 152–329 |
| PARAMETER (units) | Topalgic® 50 mg (mean ± 0.5 st. dev.) (–)-O-demethyltramadol | Tramadol LP 200 mg (mean ± 0.5 st. dev.) (–)-O-demethyltramadol | |
|---|---|---|---|
| AUC∞ (ng.h/ml) | 933 ± 0.5310 | 1022 ± 0.5421 | 98–119 |
| AUC24 h (ng.h/ml) | 690 ± 0.5191 | 745 ± 0.5286 | 97–115 |
| Cmax (ng/ml) | 43 ± 0.5 14 | 46 ± 0.5 18 | 96–119 |
| Cmin (ng/ml) | 22 ± 0.5 10 | 16 ± 0.5 8 | 56–79 |
| Tmax (h) | 1.5 (0.5–6.0) | 10.0 (6.0–16.0) | – |
| T1/2 (h) | 6.4 ± 0.5 1.9 | 9.9 ± 0.5 2.7 | 140–178 |
| Fluctuation | 63 ± 0.5 11 | 66 ± 0.5 11 | 178–289 |
After repeated dosing, there was no significant difference between the AUC of the two drug formulations. The 95% confidence intervals obtained on the ratios for AUC8 and AUCô were within the accepted limits for bioequivalence.
The Cmax was predictably lower after the administration of 50 mg of immediate release tramadol compared to 200 mg of the sustained release form. Fluctuation and Cmin, in plasma concentrations, calculated from the pharmacokinetic profile corresponding to the last administration of the immediate release product, were similar for both formulations.
Discussion
Tramadol is well established in the treatment of chronic pain and is classified as a step 2 compound on the World Health Organization pain treatment ladder. Because it is effective and well-tolerated the use of tramadol has increased substantially in a broad range of malignant and nonmalignant pain conditions [27, 28]. However, its relatively short plasma half-life requires frequent dosing (at least four times a day), which is generally associated with a poor compliance. Therefore, tramadol is a good candidate for administration in slow release form. However, the pharmacokinetic evaluation of this type of formulation is made more difficult by the formation of an active metabolite (O-demethyltramadol) with a slightly longer plasma half-life than the parent compound, and by its chiral structure, giving rise to enantiomers. Accordingly, a stereospecific analytical method was developed to evaluate the pharmacokinetics of drug and metabolite given as a sustained release formulation.
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) (—)
After a single dose administration sustained release tramadol demonstrated a significantly longer Tmax than the immediate release capsule. The relative bioavailability of the formulations was comparable with their respective 95% confidence intervals for the ratios of AUC∞ and AUCt being entirely within the accepted equivalence range of 0.8–1.25. Moreover, the present study demonstrates that concomitant food intake does not affect the pharmacokinetics of the drug given in the sustained release form, which enhances its ease of use by the patient.
Following repeated dosing, bioequivalence between the two formulations of tramadol was also found. The sustained release form also produced significantly longer Tmax and sustained plasma drug concentrations for at least 24 h. Lintz et al. has demonstrated that a plasma concentration of total tramadol (the sum of the [+]- enantiomer and [–]- enantiomer) of 100 ng ml−1 is clinically effective in the treatment of mild to moderate pain [10]. In the present, the plasma concentrations of total tramadol given in its sustained release form were consistently above 100 ng ml−1 for 24 h, and should produce analgesia over the whole of this period. These findings are supported by the results of a phase 3 clinical trial in the treatment of osteoarthritis [29].
In conclusion, this new sustained release form of tramadol has suitable pharmacokinetic characteristics to be administered once-a-day as an effective and safe treatment for pain.
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