Bioavailability and Bioequivalence of Two Oral Formulations of Alendronate Sodium 70 mg: An Open-Label, Randomized, Two-Period Crossover Comparison in Healthy Korean Adult Male Volunteers

Abstract

Background: Alendronate sodium is a bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence. Objectives: The alms of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population. Methods: This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal intern view, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC(0-t), AUC(0-infinity), C(max) T(max), t(1/2), and the elimination constant (k(e)), were determined using noncompartmental analysis. The formulations were considered bloequivalent if the 90% CI ratios for C(max) and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA). Results: Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19-28 years]; height, 175.9 [5.4] cm [range, 162.0-185.0 cm]; and weight, 71.2 [9.5] kg [range, 61-96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC(0-t), AUC(0-infinity), and C(max) were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T(max) was 1.09 hours (0.5-2.0 hours), and the mean (SD) of t(1/2) and k(e) were 2.04 (0.97) hours and 0.34 (0.71.) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study. Conclusions: Single doses of these formulations of alendronate sodium 70 mg met the criteria for bioequivalence. No statistically significant differences in AUC(0-t), AUC(0-infinity), and C(max) were found in this healthy Korean adult male population. (Clin Ther. 2009;31: 1037-1045) (C) 2009 Excerpta Medica Inc.