Celecoxib-tramadol co-crystal: A Randomized 4-Way Crossover Comparative Bioavailability Study.

Purpose: Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure.
Methods: This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were C _max , AUC _0-T , and AUC _0-∞, which were also calculated normalized to the dose. T _max was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the C _max , AUC _0-T , and AUC _0-∞ was based on ln-transformed data, and T _max was rank-transformed.
Findings: Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower C _max , reduced AUCs, and a faster T _max . The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (C _max ), respectively; 1930, 2348, and 1929 ng • h/mL (AUC _0-T ); and 1.5, 3.0, and 2.5 hours (T _max ). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower C _max and AUCs as well as a longer T _max . Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for C _max ; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC _0-T ; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for T _max. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4.
Implications: The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)