Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration.

ABSTRACT

PURPOSE: To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. METHODS: This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. RESULTS: Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. CONCLUSION: The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or "cleared," into bone. The absolute bioavailability of orally administered risedronate is approximately 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.