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Seoul, South Korea

Yim S.-V.,Kyung Hee University | Lee K.-T.,Kyung Hee Drug Analysis Center | Lee K.-T.,Kyung Hee University
International Journal of Clinical Pharmacology and Therapeutics

Background: 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. Objectives: 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. Methods: 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 Cmax, AUC0-12h and AUC0-∞ 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). Results: 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/m 2)) was enrolled and completed the study. The mean values for C max, tmax, AUC0-12h, and AUC 0-∞ with the test formulation of levodropropizine were 331.51 ng×h/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 Cmax (92.74 - 111.24), AUC 0-12h (104.31 - 113.67) and AUC0-∞ (103.87 - 113.57) were within the predetermined range for the assumption of bioequivalence. No serious adverse events were reported. Conclusions: 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. © 2013 Dustri-Verlag Dr. K. Feistle. Source

Seo J.-H.,Kyung Hee University | Park J.-S.,Kyung Hee Drug Analysis Center | Jo M.-H.,Kyung Hee University | Park M.-S.,Kyung Hee Drug Analysis Center | And 8 more authors.
Biomedical Chromatography

A rapid, simple and fully validated LC-MS/MS method was developed and validated for the determination of megestrol acetate in human plasma using tolbutamide as an internal standard (IS) after one-step liquid-liquid extraction with methyl-tert-butyl-ether. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring mode by monitoring the transitions m/z 385.5→267.1 for megestrol acetate and m/z 271.4→155.1 for IS. Chromatographic separation was performed on a YMC Hydrosphere C18 column with an isocratic mobile phase, which consisted of 10mm ammonium formate buffer (adjusted to pH 5.0 with formic acid)-methanol (60:40, v/v) at a flow rate of 0.4mL/min. The achieved lower limit of quantitation (LLOQ) was 1ng/mL (signal-to-noise ratio>10) and the standard calibration curve for megestrol acetate was linear (r>0.99) over the studied concentration range (1-2000ng/mL). The proposed method was fully validated by determining its specificity, linearity, LLOQ, intra- and inter-day precision and accuracy, recovery, matrix effect and stability. The validated LC-MS/MS method was successfully applied for the evaluation of pharmacokinetic parameters of megestrol acetate after oral administration of a single dose 800mg of megestrol acetate (Megace™) to five healthy Korean male volunteers under fed conditions. © 2012 John Wiley & Sons, Ltd. Source

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