Pharmacokinetics of Tramadol and Celecoxib in Japanese and Caucasian Subjects Following Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label Study

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 44; no. 1; pp. 63 - 75
• Main Authors: Dooner, Helen, Mundin, Gill, Mersmann, Sabine, Bennett, Carla, Lorch, Ulrike, Encabo, Mercedes, Escriche, Marisol, Encina, Gregorio, Smith, Kevin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2019
• Subjects: Administration, Oral; Adult; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Asian People - genetics; Biomedical and Life Sciences; Biomedicine; Celecoxib - administration & dosage; Celecoxib - pharmacokinetics; Cohort Studies; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Combinations; Female; Human Physiology; Humans; Male; Medical Biochemistry; Original; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Tramadol - administration & dosage; Tramadol - pharmacokinetics; White People - genetics
• ISSN: 0378-7966; 2107-0180; 2107-0180
• DOI: 10.1007/s13318-018-0491-9

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 (AUC t ) 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.