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

• Published in: Clinical therapeutics Vol. 43; no. 6; pp. 1051 - 1065
• Main Authors: Cebrecos, Jesús, Carlson, James D., Encina, Gregorio, Lahjou, Mounia, Sans, Artur, Sust, Mariano, Vaqué, Anna, Morte, Adelaida, Gascón, Neus, Plata-Salamán, Carlos
• Format: Journal Article
• Language: English
• Published: Bridgewater Elsevier Inc 01.06.2021; Elsevier Limited
• Subjects: Acute pain; Analgesics; Bioavailability; Celecoxib; Celecoxib/tramadol; Clinical medicine; Co-crystal; Comparative pharmacokinetics; Crystallization; Dosage; Drug dosages; E-58425; FDA approval; Internal Medicine; Pain; Pharmaceuticals; Pharmacokinetics; Plasma; Statistical analysis; Tramadol; New York; United States > US; E-58425; Comparative pharmacokinetics; Celecoxib/tramadol; Acute pain; Bioavailability; Co-crystal
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2021.04.002

•Celecoxib-tramadol co-crystal (CTC) is a first-in-class API-API co-crystal.•Celecoxib absorption is inhibited when co-administered with tramadol.•Celecoxib absorption interference is minimized with CTC.•CTC do not result in higher systemic exposure compared to tramadol or celecoxib.•This study validates the dosing regimen for a subsequent factorial Phase 3 study. 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. 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 Cmax, AUC0–T, and AUC0–∞, which were also calculated normalized to the dose. Tmax 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 Cmax, AUC0–T, and AUC0–∞ was based on ln-transformed data, and Tmax was rank-transformed. 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 Cmax, reduced AUCs, and a faster Tmax. 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 (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0–T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. 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.