ABSTRACT
An extended-release trazodone HCl formulation, Trazodone Contramid OAD (TzCOAD), was developed as scored 150-mg and 300-mg caplets for once-daily administration. Dose proportionality of intact and bisected caplets (dose range, 75-375 mg) was evaluated in a single-dose, randomized, 5-way crossover study. Plasma trazodone and m-chlorophenylpiperazine (mCPP) levels were determined using a validated liquid chromatography-tandem mass spectroscopy method. Dose proportionality was assessed based on confidence intervals for logarithmically transformed, dose-normalized maximum plasma concentration (C(max)), area under the plasma concentration versus time data pairs (AUC(0-t)), and area under the curve from time 0 to infinity (AUC(0-∞)) in relation to the acceptance range of 80% to 125% (bioequivalence approach). The power method, combined with confidence interval criteria, was also used to assess proportionality. The conclusion of dose proportionality was generally supported using the bioequivalence approach. Based on the power model, values of the slope and corresponding 90% confidence interval for trazodone C(max), AUC(0-t), and AUC(0-∞) were 0.948 (0.899-0.997), 0.920 (0.875-0.964), and 0.913 (0.867-0.958), respectively. All were within the acceptance interval (0.861-1.139). Results for mCPP also fell within the acceptance interval. TzCOAD exhibits linear pharmacokinetics over doses ranging from 75 to 375 mg and maintains its controlled-release properties when the caplets are bisected along the score line.
Subject(s)
Antidepressive Agents, Second-Generation/administration & dosage , Antidepressive Agents, Second-Generation/pharmacokinetics , Trazodone/administration & dosage , Trazodone/pharmacokinetics , Adult , Antidepressive Agents, Second-Generation/adverse effects , Antidepressive Agents, Second-Generation/blood , Cross-Over Studies , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/adverse effects , Delayed-Action Preparations/pharmacokinetics , Dose-Response Relationship, Drug , Female , Half-Life , Humans , Male , Models, Biological , Models, Statistical , Piperazines/blood , Tablets , Therapeutic Equivalency , Trazodone/adverse effects , Trazodone/blood , Young AdultABSTRACT
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.
Subject(s)
Analgesics, Opioid/pharmacokinetics , Tramadol/pharmacokinetics , Administration, Oral , Adolescent , Adult , Analgesics, Opioid/administration & dosage , Area Under Curve , Cross-Over Studies , Delayed-Action Preparations , Drug Administration Schedule , Female , Humans , Male , Tablets , Time Factors , Tramadol/administration & dosage , Young AdultABSTRACT
A three-way crossover study in 27 human volunteers was conducted to characterize the pharmacokinetics and to assess the dose proportionality of 100 mg, 200 mg and 300 mg strengths of a novel once-a-day tramadol controlled-release tablet (Tramadol Contramid OAD) following single-dose administration. Serial blood samples were collected at predefined timepoints over a 48 h period and racemic tramadol and O-desmethyltramadol concentrations in plasma were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using noncompartmental methods. Following dose normalization and logarithmic transformation of concentration-dependent parameters, the results were compared using analysis of variance (ANOVA). The residual variability thereby obtained was used to construct 90% classical confidence intervals. The two one-sided tests procedure was used for all pairwise comparisons. Dose proportionality was concluded since the 90% CI for the ratio of geometric means was included in the acceptance range of 0.80-1.25 for all comparisons.
