Dataset Information

Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

ABSTRACT: AIMS:Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination. METHODS:Healthy adults aged 18-55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). RESULTS:Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml-1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml-1 (mean cumulative area under the plasma concentration-time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml-1 ; 2183, 3093 and 2856 ng h ml-1 ; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. CONCLUSION:PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.

SUBMITTER: Videla S

PROVIDER: S-EPMC5698592 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

Videla Sebastián S Lahjou Mounia M Vaqué Anna A Sust Mariano M Encabo Mercedes M Soler Lluis L Sans Artur A Sicard Eric E Gascón Neus N Encina Gregorio G Plata-Salamán Carlos C

British journal of clinical pharmacology 20170920 12

<h4>Aims</h4>Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination.<h4>Methods</h4>Healthy adults aged 18-55 years were orally administered four treatments under fasted ...[more]

PMID: 28810061

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Project description:Background and objectivesCo-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class active pharmaceutical ingredient (API-API) co-crystal of rac-tramadol.HCl and celecoxib in a 1:1 molecular ratio (100 mg CTC: 44 mg rac-tramadol.HCl and 56 mg celecoxib). Tramadol and celecoxib pharmacokinetics are modified after CTC administration versus administration of reference products. This randomised, open-label, crossover, phase 1 study assessed CTC pharmacokinetics, dose proportionality, safety and tolerability in Japanese and Caucasian subjects.MethodsCTC (100, 150 and 200 mg) was administered orally to healthy Japanese/Caucasian subjects. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were determined pre-dose and up to 48 h post-dose. Maximum observed plasma concentration (Cmax), and area under the plasma concentration-time curve from dosing to last measurable concentration (AUCt) and from dosing extrapolated to infinity (AUC∞) were evaluated. Dose proportionality was assessed in a dose-adjusted bioavailability analysis of variance and in a power model. Inter-cohort comparability of pharmacokinetic exposure was confirmed if the ratio (Japanese cohort/Caucasian cohort) of geometric least-squares means and corresponding 90% confidence intervals were 80-125%. Post hoc weight-adjusted comparability analyses were performed. Safety was assessed throughout.ResultsSixty subjects (21 males/9 females per cohort) were randomised; 57 completed the study. Cohorts were age and BMI matched; there were expected inter-cohort weight differences. Exposure to each analyte increased in both cohorts with increasing CTC dose. Tramadol's pharmacokinetic exposure was comparable between cohorts after adjusting for body weight; the pharmacokinetic exposure of O-desmethyltramadol and celecoxib was increased in Japanese subjects.ConclusionsDifferences in pharmacokinetics were not sufficient to suggest that CTC dose adjustment is required in Japanese subjects.Clinical trial registrationEudraCT: 2015-003071-29.

Project description:Background and objectiveCo-Crystal of Tramadol-Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions.MethodsHealthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed.ResultsThirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O-desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration (Cmax) and extrapolated area under the plasma concentration-time curve to infinity (AUC∞) were within the pre-defined range for comparative bioavailability (80-125%). For celecoxib, Cmax and AUC∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98-146.49) and 129.34% (121.78-137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions.ConclusionsAs reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O-desmethyltramadol bioavailability.Clinical trial registration number152052 (registered with the Therapeutic Products Directorate of Health Canada).

Project description:Background and objectivesYLB113 is being developed as a biosimilar of the antitumor necrosis factor-alpha antagonist etanercept, which is approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) and other chronic immune-mediated inflammatory diseases. An open-label, crossover, pharmacokinetic study was conducted to compare the relative bioavailability and safety of YLB113 and the etanercept reference product (RP) Enbrel®.MethodsHealthy male subjects aged 18-50 years were randomized to receive a single subcutaneous dose of YLB113 in one period and the etanercept RP in another period. A washout period of 28 days separated the two treatment periods. Blood samples were collected for pharmacokinetic analysis predose and until 480 h postdose during both periods.ResultsOverall, 52 subjects were enrolled, including 51 subjects who completed the first period and 43 subjects who completed the second period. The 90% confidence intervals for the least squares means derived from an analysis of the log-transformed pharmacokinetic parameters maximum serum concentration (Cmax), area under the serum concentration-time curve (AUC) from 0 to the last measurable concentration (AUC(0-t)) and AUC from 0 to infinity (AUC(0-∞)) for etanercept were between the limits of 80 and 125%. Thus, YLB113 met the bioequivalence criterion. YLB113 and the etanercept RP were well tolerated, with 24 subjects reporting 53 adverse events, including 42 mild and 11 moderate events. Treatment-emergent adverse events were reported by 14 and 16 subjects following the administration of YLB113 and the etanercept RP, respectively.ConclusionsA single dose of YLB113 exhibited pharmacokinetic and safety profiles comparable with those of the etanercept RP in healthy adult male subjects. Therefore, YLB113 and the etanercept RP can be considered bioequivalent. These findings support the continued development of YLB113 for use in patients with RA.Jordan food & drug administration unique trial number31/Clinical/2018.

Dataset Information

Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

Publications

Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

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