Poster Number-69 - CELECOXIB-TRAMADOL HYDROCHLORIDE CO-CRYSTAL SAFETY, TOLERABILITY, AND DIFFERENTIAL PHARMACOKINETICS: A SUMMARY OF FIVE PHASE 1 RANDOMIZED CLINICAL TRIALS

Poster Abstracts

Author(s)

CS

Craig Sponseller, MD

Chief Medical Officer
Kowa Pharmaceuticals America, Inc.
Montgomery, Alabama
JC

Jesús Cebrecos, MD

Clinical Investigation Physician
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
GE

Gregorio Encina, PhD

Head of Bioanalysis and Drug Metabolism/Pharmacokinetics
Esteve Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
NG

Neus Gascón, MD

Global Drug Safety & PV Head EU QPPV
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
AM

Adelaida Morte, MD

Clinical Investigation Physician
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
CP

Carlos Plata-Salamán, MD

External Advisor
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
AS

Artur Sans, RN

Clinical Trial Monitor
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
MS

Mariano Sust, MD

Clinical Biostatistician
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
AV

Anna Vaqué, MD

Medical Drug Safety Officer & back up EUQPPV
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain
SV

Sebastián Videla, MD

Clinical Research Physician
ESTEVE Pharmaceuticals S.A.
Barcelona, Catalonia, Spain

CELECOXIB-TRAMADOL HYDROCHLORIDE CO-CRYSTAL SAFETY, TOLERABILITY, AND DIFFERENTIAL PHARMACOKINETICS: A SUMMARY OF FIVE PHASE 1 RANDOMIZED CLINICAL TRIALS

Purpose: Celecoxib and tramadol hydrochloride (Seglentis^®; CTC) is the first co‑crystal analgesic for acute pain. Seglentis^® received US Food and Drug Administration approval in October 2021.¹ Phase 1 pharmacokinetic (PK) and safety data are summarized.

Methods: Of five randomized, open-label studies,²^–6 three evaluated single‑^2,3,6 and multi‑dose³ CTC 200 mg (88 mg tramadol hydrochloride/112 mg celecoxib) versus individual or concomitant US6/EU²^–5 reference products (immediate‑release tramadol hydrochloride 100 mg and celecoxib 100 mg). One study assessed CTC bioavailability under fed/fasting conditions;⁴ another compared PK in Japanese and white healthy volunteers.⁵ Data reported include cumulative area under the plasma concentration–time curve (AUC_0–T), maximum plasma concentration (C_max), and time to C_max (T_max). C_max and AUC_0–T values are arithmetic mean (% coefficient of variation [%CV]), T_max values are median (minimum–maximum [min–max]).

Results: For tramadol, C_max was lower, AUC₀_–T similar, and T_max longer with CTC versus tramadol hydrochloride alone or concomitantly with celecoxib. In the study that compared CTC to US reference products, mean (%CV) C_max for tramadol was 214 (29), 305 (23), and 312 (22) ng/mL, for CTC, tramadol hydrochloride alone, and for concomitant administration of tramadol hydrochloride and celecoxib, respectively. Mean (%CV) tramadol AUC₀_–T was 2507 (36), 2709 (34), and 2888 (34) ng∙h/mL, for the same groups. Median (min–max) tramadol T_max was 3.0 (1.25–8.0), 2.0 (0.75–3.0), and 1.9 (1.0–6.0) hours, for CTC, tramadol hydrochloride alone, and concomitant administration of tramadol hydrochloride and celecoxib, respectively.⁶
For celecoxib, C_max and AUC₀_–T were reduced and T_max shorter with CTC versus celecoxib alone. Higher C_max, shorter T_max, and similar AUC₀_–T were observed with CTC compared with concomitant administration of tramadol hydrochloride and celecoxib. For the study that evaluated CTC versus US reference products, mean (%CV) C_max for celecoxib was 259 (34), 318 (47), 165 (46) ng/mL, from CTC, celecoxib alone, and concomitant celecoxib and tramadol hydrochloride administration, respectively. AUC₀_–T was 1930 (41), 2348 (40), and 1929 (38) ng∙h/mL, for the same groups. T_max was 1.5 (0.75–6.0), 3.0 (1.25–8.0), and 2.5 (1.0–12.0) hours, for CTC, celecoxib alone, and concomitant celecoxib and tramadol hydrochloride administration, respectively.⁶
As for the reference product, food increased celecoxib bioavailability from CTC; tramadol was unaffected. Differences were not suggestive of requirements for dose adjustment/recommendations related to meal times. Differences between Japanese and white healthy volunteers were also not suggestive of a need for dose adjustment.
Safety was consistent with that of reference products, with similar types of adverse events and no serious adverse events or deaths.

Conclusion: PK improved with CTC versus tramadol hydrochloride and celecoxib alone or concomitantly. The clear interaction between concomitant tramadol hydrochloride and celecoxib, resulting in reduced celecoxib absorption, was minimized with CTC. Overall, results were consistent across Phase 1 studies and indicate that CTC has differential PK, showing that CTC is not substitutable by concomitant US/EU tramadol hydrochloride and celecoxib.

References: 1. Seglentis® (celecoxib and tramadol hydrochloride) US prescribing information (last updated Oct 2021)
2. Videla S et al. Br J Clin Pharmacol 2017;83:2718–28
3. Videla S et al. Br J Clin Pharmacol 2018;84:64–78
4. Encina G et al. Clin Drug Investig 2018;38:819–27
5. Dooner H et al. Eur J Drug Metab Pharmacokinet 2019;44:63–75
6. Cebrecos J et al. Clin Ther 2021;43:1051–65

Learning Objectives:

Describe the differential pharmacokinetics of celecoxib-tramadol hydrochloride co-crystal compared with concomitant administration of reference products
Outline the ways in which the pharmacokinetics of celecoxib-tramadol hydrochloride co-crystal are improved compared with reference products
Detail the clinical implications of the improved pharmacokinetics of celecoxib-tramadol hydrochloride co crystal compared with concomitant administration of reference celecoxib and tramadol hydrochloride, including that these are not substitutable