Pooling of Clodronate Urinary Excretion Data: A New Pharmacokinetic Method to Study Drugs with Highly Variable Gastrointestinal Absorption

• Published in: Journal of bone and mineral research 1997-01, Vol.12 (1), p.66-71
• Main Authors: Castrén‐Kortekangas, Päivi, Löyttyniemi, Eliisa, Liukko‐Sipi, Sirpa, Juhakoski, Auni, Smal, Jaana, Laitinen, Kalevi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adolescent; Adult; Analgesics, Non-Narcotic - administration & dosage; Analgesics, Non-Narcotic - pharmacokinetics; Analgesics, Non-Narcotic - pharmacology; Analgesics, Non-Narcotic - urine; Analysis of Variance; Area Under Curve; Biological and medical sciences; Biological Availability; Capsules - metabolism; Capsules - standards; Clodronic Acid - administration & dosage; Clodronic Acid - pharmacokinetics; Clodronic Acid - pharmacology; Clodronic Acid - urine; Cross-Over Studies; Female; Follow-Up Studies; General and cellular metabolism. Vitamins; Half-Life; Humans; Intestinal Absorption - drug effects; Intestinal Absorption - physiology; Male; Medical sciences; Pharmacology. Drug treatments; Reference Standards; Reproducibility of Results; Software; Tablets - metabolism; Tablets - standards; Therapeutic Equivalency
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.1997.12.1.66

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 research and in clinical use of these drugs. We conducted a randomized, two‐period cross‐over pharmacokinetic (phase I) study to assess the relative bioavailability of two different clodronate preparations: an 800 mg tablet and a 400 mg capsule. Urinary excretion of clodronate correlates with gastrointestinal absorption. To minimize the confounding effect of the high variability of gastrointestinal absorption, we chose as the primary parameter the cumulative amount of clodronate excreted into urine (Ae0‐t) during 9 days (7 days of treatment, 2 days of follow‐up). The 90% confidence interval calculated for the population medians of Ae0‐t was 0.83–1.09, well within the 90% confidence interval stipulated for bioequivalence for the area under the curve values (0.80–1.25). This new procedure for pooling urinary excretion data offered 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.