POOLING OF CLODRONATE URINARY-EXCRETION DATA - A NEW PHARMACOKINETIC METHOD TO STUDY DRUGS WITH HIGHLY VARIABLE GASTROINTESTINAL ABSORPTION

Gastrointestinal absorption of bisphosphonates is highly variable from individual to individual (between-subject variation) and from day to day (within-subject variation), a fact that creates problems both in r esearch and in clinical use of these drugs, We conducted a randomized, two-period cross-over pharmacokinetic (phase I) study to assess the r elative bioavailability of two different clodronate preparations: an 8 00 mg tablet and a 400 mg capsule, Urinary excretion of clodronate cor relates with gastrointestinal absorption, To minimize the confounding effect of the high variability of gastrointestinal absorption, we chos e as the primary parameter the cumulative amount of clodronate excrete d into urine (A(e0-t)) during 9 days (7 days of treatment, 2 days of f ollow-up), The 90% confidence interval calculated for the population m edians of A(e0-t) was 0.83-1.09, well within the 90% confidence interv al stipulated for bioequivalence for the area under the curve values ( 0.80-1.25), This new procedure for pooling urinary excretion data offe red a clear advantage over previous methods, and thus could presumably be used to study other drugs as well that are not metabolized and may show highly variable gastrointestinal absorption.