Comparative Bioavailability of Tramadol Contramid® Once-A-Day and Tramadol Immediate-Release Tablets Presented at: The American Academy of Pain Medicine, 23rd Annual Meeting, February 7-10, 2007, New Orleans David Karhu, BSc and Sylvie Bouchard, MD, PhD Labopharm Inc., Laval, Québec, Canada ABSTRACT RESULTS Multiple-Dose Study DISCUSSION The bioavailability of Tramadol Contramid® Once a day (OAD) tablets and tramadol immediate-release (IR) Single-Dose Study A once-daily formulation of tramadol (Ultram® ER, Ortho-McNeil Pharmaceutical Inc.) was recently introduced to the US Figure 3. Mean (SD) steady-state plasma tramadol concentrations on the market.(10) Its pharmacokinetic profile is as follows: (Ultram®) tablets was compared following single-dose administration and at steady state in two separate Figure 1. Mean (SD) plasma tramadol concentrations following single-dose fifth day of multiple-dose administration of 200 mg Tramadol Contramid® • The overall extent of exposure to tramadol is bioequivalent between tramadol ER and tramadol IR following single- and studies. Both the single-dose and multiple-dose studies had an open-label, randomized, 2-way crossover administration of 200 mg Tramadol Contramid® OAD tablets and 50 mg OAD tablets and 50 mg tramadol IR tablets for 5 days multiple-dose administration.(10,11) design. Twenty-six healthy adult subjects were enrolled in each study. All subjects completed the multiple- tramadol IR tablets • Tramadol ER exhibits a lag time of approximately 2 hours during which no appreciable drug absorption occurs, and dose study and 24 subjects completed the single-dose study. In both studies, Tramadol Contramid® OAD was 500 maximum plasma levels are attained >10 hours post-dose.(10,11) 500 ® administered orally as a 200 mg tablet dose once daily and tramadol IR was administered as one 50 mg tablet Tramadol Contramid OAD 200 mg tablet x 1 dose • Following single-dose administration of tramadol ER, minimum effective plasma levels (>100 ng/mL) are not attained Tramadol IR 50 mg tablet q6h x 4 doses Tramadol Concentration (ng/mL) every 6 hours. In the multiple-dose study, each treatment was administered for five consecutive days. Plasma until approximately 6 hours post-dose.(11) Tramadol Concentration (ng/mL) tramadol and O-desmethyltramadol levels were determined using validated LC/MS/MS methods. Primary 400 400 • Mean steady-state concentrations for tramadol ER are maintained above the lowest mean concentration attained for tramadol IR for approximately 70% of the dosing interval.(10) pharmacokinetic parameters [single-dose: AUC0-t, AUC0-inf and Cmax; steady-state: AUC0-24 and Cmax] were • Steady state is attained within 4 days for tramadol ER.(10) assessed by ANOVA. In both studies, the AUC parameters met bioequivalence criteria (90% CI within 300 300 80-125%) and the Cmax of Tramadol Contramid® OAD was lower than that of tramadol IR. Following single- dose administration, the mean tramadol concentrations at 1 hour post-dose were within the therapeutic range 200 (100-300 ng/mL). Steady-state concentrations were attained within 48 hours following the first dose of 200 Tramadol Contramid® OAD. Peak-to-trough variation was 77% for Tramadol Contramid® OAD, compared with Minimum therapeutic level 91% for tramadol IR. Tramadol Contramid® OAD 200 mg achieves therapeutic plasma concentrations within Minimum therapeutic level 100 CONCLUSIONS 100 ® 1 hour of administering the first dose and remains above the minimum therapeutic concentration (>100 ng/mL) Tramadol Contramid OAD 200 mg tablet QD Tramadol IR 50 mg tablet QID q6h • Tramadol Contramid® OAD 200 mg tablets provide equivalent exposure for 24 hours; exposure is equivalent to tramadol IR 50 mg every 6 hours with respect to AUC, with a lower Cmax. 0 0 0 4 8 12 16 20 24 compared with tramadol IR tablets (Ultram®) following both single- and 0 4 8 12 16 20 24 Time (h) 28 32 36 40 44 48 Time (h) multiple-dose administration. INTRODUCTION • Both products were well tolerated. • Following single- and multiple-dose administration, Cmax for Tramadol • Both products were well tolerated. Tramadol is a centrally acting, synthetic analgesic used in the management of pain.(1) Tramadol and its M1 metabolite, • The 90% confidence intervals for AUC0-t, AUC0-24, AUC0-∞ were within the 80-125% range (Table 1). Thus, Tramadol Contramid® • Analysis of trough concentrations on Days 3, 4 and 5 showed no statistically significant differences for either Tramadol Contramid® OAD 200 mg or tramadol IR 50 mg. Thus, steady state was attained within 48 h for both products. Contramid® OAD 200 mg is lower than that for tramadol IR 50 mg. O-desmethyltramadol, act as opioid agonists through selective binding to the µ-opioid receptor and weak inhibition of norepinephrine OAD 200 mg is bioequivalent to tramadol IR 50 mg with respect to extent of exposure. • The 90% confidence interval for AUCss was within 80-125% (Table 2). Therefore, bioequivalence with respect to extent of exposure and serotonin re-uptake.(2-4) This second mode of action is thought to complement opioid receptor binding, thereby increasing • Cmax was lower for Tramadol Contramid® OAD 200 mg compared with tramadol IR 50 mg. • The mean tramadol concentration remained above 100 ng/mL 24 hours after a single dose of Tramadol Contramid® OAD 200 mg. was concluded. • Following single-dose administration, the initial absorption of tramadol analgesic activity.(5) Since tramadol has a relatively short half-life, immediate-release formulations must be administered at least four • Cmax was lower for Tramadol Contramid® OAD 200 mg compared with tramadol IR 50 mg. times a day. In general, dosing frequency has been shown to be inversely proportional to compliance.(6,7) The lack of compliance • The mean tramadol plasma concentrations at 1 hour post-dose were within the therapeutic range (100-300 ng/mL): 110 ± 40 ng/mL • Tramadol Contramid® OAD 200 mg had less peak-to-trough variability than tramadol IR 50 mg. from Tramadol Contramid® OAD 200 mg is rapid (comparable to for Tramadol Contramid® OAD 200 mg and 158 ± 54 ng/mL for tramadol IR 50 mg. associated with high-frequency dosing regimens can result in inconsistent plasma drug concentrations and, accordingly, less • Similar results were obtained for the metabolite (results not shown). • Mean steady-state tramadol concentrations for Tramadol Contramid® OAD 200 mg were maintained above the lowest mean concentration attained for tramadol IR 50 mg for 83% of the dosing interval. Tramadol IR 50 mg). consistent analgesia. Modified-release formulations have the potential to improve patient compliance by simplifying the dosing • Similar results were obtained for the metabolite (results not shown). regimen. However, the rate of drug release from modified-release formulations is generally slower than for immediate-release formulations. A novel once-daily tramadol formulation recently developed by Labopharm Inc. uses Contramid® technology that is Table 1. Mean (±SD) tramadol single-dose pharmacokinetic parameters and results • Effective plasma concentrations are attained within 1 h of dosing and of comparison [n=24] based on chemically cross-linked high-amylose starch. Using a dual matrix delivery system, Tramadol Contramid® OAD tablets were Table 2. Mean (±SD) steady-state tramadol pharmacokinetic parameters maintained for a full 24-h post-dose period following single-dose designed to attain therapeutic levels (>100 ng/mL)(8) within 2 hours and provide continuous drug delivery and corresponding pain and results of comparison [n=26] relief over 24 hours following a single dose, and to provide steady-state levels between 100 and 300 ng/mL with a once-daily dosing Tramadol ® Contramid OAD Tramadol IR Ratio of Least-Squares Means administration of Tramadol Contramid® OAD 200 mg. PK Parameter 200 mg tablet 50 mg tablet (90% CI) regimen. Three strengths were developed: 100 mg, 200 mg and 300 mg. Comparative bioavailability studies were conducted to Tramadol Ratio of evaluate the performance of the 200 mg tablets following single-dose and multiple-dose administration. AUC0-t (ng·h/mL) AUC0-24 (ng·h/mL) 5582 ± 2535 4382 ± 1812 5851 ± 2456 4429 ± 1620 92.8 (87.2 – 98.7) 96.0 (90.5 – 101.8) PK Parameter ® Contramid OAD 200 mg tablet Tramadol IR 50 mg tablet Least-Squares Means (90% CI) • Steady state is attained within 48 h following initiation of dosing with OBJECTIVES AUC0-∞ (ng·h/mL) 5748 ± 2661 6008 ± 2607 93.1 (87.5 – 99.2) AUCss (ng·h/mL) Cmax (ng/mL) 5991 ± 1330 345 ± 73 6399 ± 1766 423 ± 97 94.7 (91.1 – 98.5) 81.8 (77.5 – 86.3) Tramadol Contramid® OAD 200 mg, allowing for titration up to the AUCRefTmax (ng·h/mL) 111 ± 112 122 ± 82 74.5 (63.4 – 87.6) • Compare the single-dose bioavailability of Tramadol Contramid® OAD (Labopharm Inc.) 200 mg tablets with tramadol IR (Ultram®) (Ortho-McNeil Pharmaceutical Inc.) 50 mg tablets administered 4 times at 6-hour intervals. Cmax (ng/mL) 256 ± 90 353 ± 118 71.6 (66.9 – 76.7) Cmin (ng/mL) 157 ± 48 190 ± 64 83.4 (78.7 – 88.4) higher doses on the third day. CRefTmax (ng/mL) 127 ± 53 190 ± 53 62.6 (52.9 – 74.0) PTF (%) 76.9 ± 20.0 91.1 ± 20.0 83.1 (75.2 – 91.9) • Assess the relative bioavailability of Tramadol Contramid® OAD 200 mg tablets and tramadol IR 50 mg tablets at steady state. t½ (h) 7.07 ± 1.42 6.03 ± 1.31 117.6 (111.8 – 123.7) HVD (h) 20.7 ± 2.6 22.0 ± 2.2 94.0 (90.1 – 98.0) -1 0.102 ± 0.020 0.120 ± 0.027 Tmax (h) # 4 (3 – 9) 1 (1 – 3) λz (h ) METHODOLOGY AUCss, area under the concentration-time curve over dosing interval at steady state; Cmax, maximum concentration; Cmin, minimum Tmax (h) # 6 (2.5 – 16) 16 (6.5 – 20) concentration; PTF, peak-to-trough fluctuation (calculated as %PTF = 100 * (Cmax – Cmin)/AUCss/24 h); HVD, half value duration Both studies were conducted in compliance with ICH GCP guidelines and in accordance with the Declaration of Helsinki. Study RefTmax (h) # - 1.25 (0.5 – 3.0) (obtained by linear interpolation between the respective concentrations above and below 50% of Cmax); Tmax, time to reach maximum protocols were approved by an independent ethics committee. The nature of each study was explained and subjects provided their C0.25h (h) 1.17 ± 2.49 3.02 ± 6.46 concentration. REFERENCES written consent before any study-related procedures were performed. C0.50h (h) 55.3 ± 33.1 64.5 ± 67.5 # median values and range presented. 1) Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs. 2000; 60: 139-76. AUC0-t, AUC0-24 and AUC0-∞, area under the plasma concentration time curve from time 0 to last observed concentration, to 24 h and Single-dose comparison extrapolated to infinity, respectively; AUCRefTmax, area under the plasma concentration time curve from time 0 to RefTmax (where 2) Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently This study had an open-label, randomized, two-way crossover design. A total of 26 healthy volunteers (22 males and 4 females) were RefTmax is time corresponding to the maximum concentration of the tramadol IR product following the initial dose (0-6 h)); Cmax, contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther 1992; 260: maximum concentration; CRefTmax, observed concentration at RefTmax; t½, apparent terminal elimination half-life; λz, apparent enrolled. Two subjects discontinued from the study: one as a result of an adverse event (vomiting) after receiving the tramadol IR terminal elimination rate constant; Tmax, time to maximum concentration; Cnh, mean tramadol plasma concentration at n hours post-dose. 275-85. product, and one because of a protocol violation. Thus, 24 subjects (21 males and 3 females) completed the study. In each study # median values and range presented. DISCUSSION 3) Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N. Complementary and period, following an overnight fast, subjects received either a single 200 mg Tramadol Contramid® OAD tablet dose or a 50 mg Tramadol Contramid® OAD tablets were designed to provide both an immediate initial release of tramadol for rapid onset of synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993; 267: 331-40. tramadol IR tablet dose 4 times at 6-hour intervals, according to the randomization scheme. Each dose was administered with analgesia, followed by controlled release of tramadol to provide analgesia over a full 24 hours after dosing. The analgesic 4) Valle M, Garrido MJ, Pavon JM, Calvo R, Troconiz IF. Pharmacokinetic-pharmacodynamic modeling of the 240 mL of water. A washout period of at least 6 days separated the last dose in Period 1 and the first dose in Period 2. Blood samples Figure 2. Mean (SD) plasma tramadol concentrations over the first efficacy of Tramadol Contramid® OAD tablets in patients with osteoarthritis has been demonstrated previously.(9) antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 20, 24, 30, 36 and 48 h post-dose for Tramadol Contramid® OAD and pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6*, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12*, 12.5, 13, Mean plasma tramadol concentrations at 0.25 and 0.50 hours post-dose were similar for Tramadol Contramid® OAD and for in rats. J Pharmacol Exp Ther 2000; 293: 646-53. 6 hours following single-dose administration of 200 mg Tramadol Contramid® 13.5, 14, 14.5, 15, 16, 18*, 18.5, 19, 19.5, 20, 20.5, 21, 22, 24, 30, 36 and 48 h post-dose for the tramadol IR product. Plasma tramadol IR. This suggests that tramadol absorption from both products starts at approximately the same time. 5) Aronson MD. Nonsteroidal anti-inflammatory drugs, traditional opioids, and tramadol: contrasting therapies for the samples were assayed using a validated LC/MS/MS method (LLOQ: tramadol, 2.91 ng/mL; O-desmethyltramadol, 0.806 ng/mL). OAD tablets and 50 mg tramadol IR tablets treatment of chronic pain. Clin Ther 1997; 19: 420-32. Pharmacokinetic parameters were calculated using noncompartmental methods. Values of PK parameters were compared using Tramadol Contramid® OAD exhibits a plasma concentration-time profile with a steep initial slope comparable to immediate- 400 release tramadol tablets, suggesting a rapid attainment of therapeutic concentrations. Immediate-release tramadol has 6) Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication ANOVA following log-transformation of the data (α = 5%). The mean square error from this ANOVA was used to construct the Tramadol Contramid® OAD 200 mg tablet x 1 dose shown analgesic effects within 1 hour of dosing with similar tramadol plasma concentrations as those measured for the compliance. Clin Ther 2001; 23: 1296-1310. conventional confidence intervals. Bioequivalence was concluded if the 90% confidence interval for the Tramadol Contramid® Tramadol IR 50 mg tablet x 1 dose OAD/tramadol IR ratio of geometric means for AUC0-t and AUC0-∞ fell within the conventional range of 80% to 125%. Tramadol Contramid® OAD within the same time frame. 7) Kruse W, Eggert-Kruse W, Rampmaier J, Runnebaum B, Weber E. Dosage frequency and drug-compliance behaviour Tramadol Concentration (ng/mL) *Blood sample collected immediately prior to the dose – a comparative study on compliance with a medication to be taken twice or four times daily. Eur J Clin Pharmacol 300 Two parameters, AUCRefTmax and CRefTmax, were calculated to compare the initial absorption phases following single-dose 1991; 41: 589-592. Multiple-dose comparison administration of the two tramadol products. The mean tramadol concentration following dosing with Tramadol Contramid® 8) Topalgic LP (Tramadol) Monograph, Dictionnaire Vidal, ed. 2004: pp. 1948-9. In this study, which had an open-label, randomized, 2-way crossover design, 26 healthy volunteers (22 males and 4 females) OAD 200 mg is 63% that of tramadol IR 50 mg at RefTmax. However, the AUC of Tramadol Contramid® OAD 200 mg is approximately 75% that of tramadol IR 50 mg at that same timepoint. Thus tramadol exposure over the initial hours 9) Mongin G, Yakusevich V, Köpe A, Shostak N, Pikhlak E, Efficacy and safety assessment of a novel once-daily tablet received a 200 mg Tramadol Contramid® OAD tablet once daily for 5 days or a 50 mg tramadol IR tablet every 6 hours for 5 days. following single-dose administration is similar for the two products. This is supported by the observation that the minimum formulation of tramadol. Clin Drug Invest 2004; 24: 545-58. Trough concentrations, measured prior to the morning dose on Days 3, 4 and 5, were used to confirm that steady state had been 200 attained. Each dose was administered with 240 mL of water, the morning dose following an overnight fast. In each period, subjects therapeutic tramadol concentration (>100 ng/mL) is attained within 1 h for both products. 10) Ultram® ER (tramadol) Prescribing Information, January 2006. received the assigned formulation according to the randomization scheme. Treatment periods were separated by a 16-day washout The mean tramadol concentration remains above 100 ng/mL 24 hours after a single dose of Tramadol Contramid® OAD 200 11) Lai JC, Sista S, Eradiri O, The pharmacokinetics of novel once daily tramadol hydrochloride extended release tablets in period. On the profile day, blood samples were collected pre-dose and at 1, 2, 3, 4, 5, 6, 9, 12, 16, 20 and 24 h post-dose for the test healthy subjects. Poster presented at AAPS Annual Meeting 2003, Salt Lake City, Utah. product and pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6*, 6.5, 7, 7.5, 8, 8.5, 9, 10, 11, 12*, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18*, 100 mg. The therapeutic effect over the full 24 hour dosing interval has been previously demonstrated in a clinical study.(9) Minimum therapeutic level 18.5, 19, 19.5, 20, 20.5, 21, 22, 23 and 24 h post-dose for the tramadol IR product. Plasma samples were assayed using a validated Steady state is attained within 2 days following once-daily administration of Tramadol Contramid® OAD 200 mg. Therefore, LC/MS/MS method (LLOQ: tramadol, 0.776 ng/mL; O-desmethyltramadol, 0.790 ng/mL). Pharmacokinetic parameters were it is possible that patients may be titrated to their optimum dose within 48 hours (which is comparable to the immediate calculated using noncompartmental methods. Values of PK parameters were compared using ANOVA following log-transformation of release formulation). the data (α = 5%). Bioequivalence was concluded if the 90% confidence interval for the Tramadol Contramid® OAD/tramadol IR ratio 0 of geometric means for AUCss fell within the conventional range of 80% to 125%. 0 1 2 3 4 5 6 Since the two tramadol formulations are bioequivalent in terms of extent of exposure at steady state, this will facilitate the ACKNOWLEDGEMENTS *Blood sample collected immediately prior to the dose Time (h) switch from tramadol IR 50 mg to Tramadol Contramid® OAD 200 mg. The authors are grateful to the staff at FARMOVS-PAREXEL, Bloemfontein, South Africa, for their assistance in the planning and conduct of these studies. This research was funded by Labopharm Inc.