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01-02-2005 | Original Research Article

Pharmacokinetic Considerations in Determining the Terminal Elimination Half-Lives of Bisphosphonates

Authors: Kenneth C. Lasseter, Arturo G. Portas, Andrew Denker, Anu Santhanagopal, Dr Anastasia Daifotis

Published in: Clinical Drug Investigation | Issue 2/2005

Abstract

Background and objective: Bisphosphonates are commonly used to treat and prevent osteoporosis. These compounds have unusual pharmacokinetic characteristics because they bind strongly to bone, and a portion becomes buried under newly formed bone. Once incorporated into bone tissue, the subsequent release during bone remodeling is probably the rate-limiting step in the terminal elimination of bisphosphonates. Because of this unique property of bisphosphonates, pharmacokinetic studies with insufficient lengths of follow-up might entirely miss the true terminal elimination phase. A terminal half-life (t_1/2γ) of approximately 11 years, similar to that of calcium and other minerals in bone, was reported from an 18-month study of alendronic acid in postmenopausal women with osteoporosis. We are not aware of any other published reports in which the elimination of a bisphosphonate has been followed for more than a few weeks post-dose. The purpose of the present study was to reanalyse the alendronic acid data to examine the effect of truncating the length of follow-up on the calculated t_1/2γ.

Patients and methods: Twenty-one postmenopausal women with osteoporosis (mean age 66 years) received intravenous alendronic acid 30mg over 4 consecutive days (7.5 mg/day), and urinary excretion of alendronic acid was monitored over the following 18–24 months. Terminal elimination half-life was originally calculated by log-linear regression of the percentage retained versus time curve between days 240 and 540 and substituting the slope of the regression line into the equation, t_1/2γ = −log 2/slope. These data were reanalysed based on the period up to 30 days.

Results: Data were sufficient for analysis of pharmacokinetics in 11 patients. A mean t_1/2γ of approximately 11 years was reported previously, based on analysis of data between days 240 and 540. Recalculating the ‘terminal’ half-life of alendronic acid using only data from the first 30 days resulted in an ‘observed’ half-life of only 11 days.

Conclusion: This analysis illustrates the importance of sufficient length of follow-up to accurately characterise the true terminal elimination half-life of bisphosphonates. The relatively short (expressed in units of days rather than years) terminal elimination half-lives reported for some bisphosphonates based on only 30 days of follow-up or less are likely to substantially underestimate the true terminal elimination half-lives.

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Title: Pharmacokinetic Considerations in Determining the Terminal Elimination Half-Lives of Bisphosphonates
Authors: Kenneth C. Lasseter
Arturo G. Portas
Andrew Denker
Anu Santhanagopal
Dr Anastasia Daifotis
Publication date: 01-02-2005
Publisher: Springer International Publishing
Published in: Clinical Drug Investigation / Issue 2/2005
Print ISSN: 1173-2563
Electronic ISSN: 1179-1918
DOI: https://doi.org/10.2165/00044011-200525020-00003

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Pharmacokinetic Considerations in Determining the Terminal Elimination Half-Lives of Bisphosphonates

Abstract

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