Pharmacokinetic Evaluation of a Fixed-Dose Combination of Pelubiprofen and Tramadol: A Randomized Crossover Relative Bioavailability Trial and a Fixed-Sequence Food-Effect Study in Healthy Volunteers

Abstract

DW-1021 is a novel fixed-dose combination salt formulation containing pelubiprofen 45 mg and tramadol hydrochloride 45.9 mg (equivalent to 40.3 mg tramadol free base). Two open-label, phase I clinical studies were conducted in healthy Vietnamese male volunteers to characterize the pharmacokinetics of DW-1021. The relative bioavailability study employed a randomized, single-dose, two-period, two-sequence crossover design (n = 14) comparing DW-1021 with co-administration of Pelubi CR (pelubiprofen 45 mg) and Zytram CR (tramadol hydrochloride 75 mg, equivalent to 65.9 mg tramadol base) under fasting conditions. The food effect study used a fixed-sequence, two-period design (n = 14) to evaluate DW-1021 under fasting and fed (high-fat, high-calorie) conditions. In the relative bioavailability study, DW-1021 resulted in lower exposure to pelubiprofen (AUC_0-t GMR: 86.68%) and generally comparable exposure to trans-OH-pelubiprofen (AUC_0-t GMR: 108.74%) compared with the reference treatment. For tramadol, unadjusted comparisons showed a higher peak concentration (C_max GMR: 192.17%) but lower overall exposure (AUC_0-t GMR: 79.30%). After dose normalization, tramadol exposure per unit dose was higher (AUC_0-t/Dose GMR: 129.58%). In the food effect study, fasting conditions were associated with higher C_max and AUC_0-t of pelubiprofen (GMRs: 109.92% and 140.48%, respectively). Food increased tramadol C_max, while AUC_0-t remained largely comparable between conditions. All adverse events were mild to moderate, and no serious adverse events were reported. In conclusion, DW-1021 exhibited analyte-dependent pharmacokinetic differences relative to the reference treatment. Food intake primarily reduced pelubiprofen exposure, while tramadol AUC_0-t was minimally affected, with a modest increase in C_max under fed conditions.