1. Pharmacokinetics of Tramadol and Celecoxib in Japanese and Caucasian Subjects Following Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label Study.
- Author
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Dooner H, Mundin G, Mersmann S, Bennett C, Lorch U, Encabo M, Escriche M, Encina G, and Smith K
- Subjects
- Administration, Oral, Adult, Analgesics, Opioid administration & dosage, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Celecoxib administration & dosage, Cohort Studies, Cross-Over Studies, Dose-Response Relationship, Drug, Drug Combinations, Female, Humans, Male, Tramadol administration & dosage, Analgesics, Opioid pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Asian People genetics, Celecoxib pharmacokinetics, Tramadol pharmacokinetics, White People genetics
- Abstract
Background and Objectives: Co-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., Methods: CTC (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 (C
max ), 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., Results: Sixty 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., Conclusions: Differences in pharmacokinetics were not sufficient to suggest that CTC dose adjustment is required in Japanese subjects., Clinical Trial Registration: EudraCT: 2015-003071-29.- Published
- 2019
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