Comparative Pharmacokinetics of a Once‐Daily Tramadol Extended‐Release Tablet and an Immediate‐Release Reference Product Following Single‐Dose and Multiple‐Dose Administration

Abstract

The pharmacokinetics of a once-daily formulation of tramadol (Tramadol Contramid OAD 200-mg tablets) following single-dose and multiple-dose administration was compared with that of an immediate-release product (tramadol IR 50-mg tablets) in 2 separate studies. In both studies, AUC parameters met bioequivalence criteria, whereas C(max) of Tramadol Contramid OAD was lower than that of tramadol IR following a 200-mg daily dosage. After single-dose administration, the mean tramadol concentration at 1 hour postdose was within the range associated with analgesic efficacy (>100 ng/mL), and the mean concentration remained above this level for the remainder of the dosing interval. Steady state was attained within 48 hours following multiple-dose administration. Tramadol Contramid OAD provides a rapid rise in plasma concentrations and an equivalent daily systemic exposure as tramadol IR, with a reduction in peak plasma concentrations.

Bioavailability and Bioequivalence

“…Suspension and solution formulations were found to provide 4.3-and 9.7-fold improvements in oral bioavailability relative to tablets, respectively, as demonstrated by comparing AUC exposures of the sulfoxide metabolite [36]. Similarly, the potent desmethyl metabolite of tramadol, a centrally acting analgesic, was monitored to compare the PK of an extended-release tablet relative to an immediate-release reference product [37]. However, in the case of the antiplatelet agent clopidogrel, neither parent drug nor pharmacologically active metabolite is present in circulation at high concentrations following oral administration.…”

Single‐Dose Pharmacokinetic Study of Tramadol Extended‐Release Tablets in Children and Adolescents

“…Tramadol binds to μ‐opioid receptors and weakly inhibits serotonin and norepinephrine reuptake. The unique synergistic action between the opioid and nonopioid components has been shown to improve the analgesic efficacy and tolerability profile of tramadol compared with acetaminophen and NSAIDs . Tramadol ER administered once daily was bioequivalent to tramadol immediate release (IR) administered 4 times daily and was efficacious using a once‐daily treatment regimen in patients with chronic pain .…”

Single‐ and multiple‐dose pharmacokinetic studies of tramadol immediate‐release tablets in children and adolescents

“…Tramadol is a synthetic, atypical, centrally acting opioid analgesic approved for the management of moderate to severe pain in adults in many countries including the United States, European Union, and Australia . It has been licensed for use in children over 1 year of age in many European countries; however, its use has been limited to children over 12 years of age . Tramadol is a racemate of two enantiomers, both contributing to analgesic activity via different mechanisms; (+)‐tramadol inhibits serotonin reuptake while (−)‐tramadol inhibits norepinephrine reuptake.…”

“…(+)‐Tramadol and its metabolite (+)‐O‐desmethyl‐tramadol (M1) are agonists of the μ‐opioid receptor. However, while tramadol binds weakly to the δ‐ and μ‐opioid receptors, its M1 metabolite is approximately 200‐fold more potent than the parent drug in µ‐opioid binding …”

“…The pharmacokinetics (PK) of tramadol IR tablets in adults is well described . Tramadol is rapidly and completely absorbed (mean absolute bioavailability of 100 mg oral dose is ∼75%) and extensively metabolized after oral administration.…”