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 aims 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 interview, 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 AUC0−t, AUC0−∞, Cmax, Tmax, t1/2, and the elimination constant (ke), were determined using noncompart-mental analysis. The formulations were considered bioequivalent if the 90% CI ratios for Cmax 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 AUC0−t, AUC0−∞ and Cmax were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of Tmax was 1.09 hours (0.5–2.0 hours), and the mean (SD) of t1/2 and ke 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 bio-equivalence. No statistically significant differences in AUC0−t, AUC0−∞, and Cmax were found in this healthy Korean adult male population. [Copyright &y& Elsevier]