Single-dose pharmacokinetics of Co-Crystal of Tramadol-Celecoxib: results of a 4-way randomized open-label Phase I clinical trial in healthy subjects

Abstract

Aim

Co-Crystal of Tramadol-Celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients (APIs) 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 [C_max]); 3039, 2979 and 3119 ng h ml^-1 (mean cumulative area under the plasma concentration–time curve [AUC_τ]); and 2.7, 1.8 and 1.8 h (median time to C_max [T_max]). For Treatments-1, -3 and -4, 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.

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