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

AimsCo‐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.MethodsHealthy 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).ResultsThirty‐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.ConclusionPK parameters of each API in CTC were modified by co‐crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.

Pharmacokinetics of multiple doses of co‐crystal of tramadol–celecoxib: findings from a four‐way randomized open‐label phase I clinical trial

“…It is unlikely, however, that this greater variability reduces the certainty of conclusions drawn around the celecoxib data in the present study. Of note, all multiple‐dose PK findings, including those for celecoxib, were consistent with the single‐dose data collected in the present study and in a separate phase I study of CTC .…”

“…In the examples above, increases in exposure are reflected in dose adjustments to maintain efficacy and safety. The first‐in‐class co‐crystal of tramadol–celecoxib (CTC) presents a different concept supported by in vitro and phase I data after a single dose ; neither tramadol nor celecoxib from CTC show increased exposure levels compared with the individual authorized tramadol or celecoxib, but rather show a change in profile that may translate into clinical benefits per se . One aspect of CTC based on its individual API PK and pharmacodynamic profiles is the hypothesis of CTC‐associated improved efficacy with reduced doses of each API.…”

“…Such effects have the potential to optimize the PK profiles, and thus efficacy and safety, of each API in CTC. In a single‐dose phase I study of CTC, the PK characteristics of tramadol and celecoxib from CTC were modified by co‐crystallization relative to IR tramadol or celecoxib alone and the open combination of these reference products . These changes in PK parameters could translate into a real therapeutic benefit, to be determined in phase II and III clinical trials.…”

The Effect of Food on Tramadol and Celecoxib Bioavailability Following Oral Administration of Co-Crystal of Tramadol–Celecoxib (CTC): A Randomised, Open-Label, Single-Dose, Crossover Study in Healthy Volunteers

“…The clinical pharmacokinetics of CTC were first characterised in two Phase 1 studies conducted in healthy male and female subjects; one assessing a single dose of CTC [ 11 ] and one assessing multiple doses [ 12 ]. In both studies, differences in the pharmacokinetics of tramadol and celecoxib were seen after administration of CTC compared with after administration of the individual reference products (immediate-release tramadol or celecoxib) alone or in free combination.…”

“…In the case of tramadol, a lower maximum observed plasma concentration ( C max ), slightly prolonged time to C max ( T max ) and similar area under the plasma concentration–time curve (AUC) were observed with CTC. In the case of celecoxib pharmacokinetics after CTC administration, celecoxib had a lower C max compared with celecoxib alone, and a faster T max compared with celecoxib alone or in free combination with tramadol [ 11 , 12 ].…”