Relative bioavailability of levodropropizine 60 mg capsule and syrup formulations in healthy male Korean volunteers: a singledose, randomized-sequence, open-label, two-way crossover study

Abstract

Levodropropizine is an oral non-opioid anti-tussive drug used in treatment of cough. A new generic 60 mg capsule formulation of levodropropizine has recently been developed. The aim of this study was to assess the pharmacokinetics and bioequivalence of the test (capsule) formulation and reference (syrup) formulation of levodropropizine (60 mg) in healthy, fasted, male Korean volunteers. This was a single-dose, randomized sequence, open-label, 2-period crossover study conducted in healthy male Korean volunteers in the fasted state at Kyung Hee University Medical Center (Seoul, Republic of Korea). A single oral dose of the test or reference formulation was followed by a 1-week washout period, after which subjects received the alternative formulation. Blood samples were collected at 0 (predose), 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after study drug administration. Plasma concentration of levodropropizine was determined using a validated liquid chromatography tandem mass spectrometry (LCMS/ MS) method. The formulations were considered bioequivalent if the 90% CIs for C(max), AUC(0-12h) and AUC(0-∞) were within the predetermined bioequivalence range (80 - 125%, according to the guidelines of the Korea Food and Drug Administration (Korea FDA)). Tolerability was evaluated throughout the study based on vital sign measurements, laboratory analysis (blood biochemistry, hematology, hepatic function and urinalysis) and subject interviews concerning adverse events (AEs). A total of 36 male Korean subjects (mean (SD) age, 23.9 (2.4) years (range 19 - 30 years); height, 176.2 (6.1) cm (range 161 - 190 cm); weight, 69.8 (9.1) kg (range 54.0 - 92.2 kg); body mass index, 22.4 (2.1) kg/m2 (range 19.1 - 28.3 kg/m2)) was enrolled and completed the study. The mean values for C(max), t(max), AUC(0-12h), and AUC(0-∞) with the test formulation of levodropropizine were 331.51 ng/ml, 0.60 hours, 784.32 ng×h/ml, and 825.82 ng×h/ml, respectively; for the reference formulation, the values were 332.81 ng/ml, 0.44 hours, 726.46 ng×h/ml, and 769.46 ng×h/ ml, respectively. The 90% CIs for the logtransformed ratios of C(max) (92.74 - 111.24), AUC(0-12h) (104.31 - 113.67) and AUC(0-∞) (103.87 - 113.57) were within the predetermined range for the assumption of bioequivalence. No serious adverse events were reported. This single-dose (60 mg) study found that the test (capsule) and reference (syrup) formulations of levodropropizine met the regulatory criterion for assuming bioequivalence in these healthy, fasted, male Korean subjects. Both formulations were well tolerated in the population studied. Korea FDA registration number: BED-1784.