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Lasseter KC, Porras AG, Denker A, et al. Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates. Clin Drug Investig. 2005;25(2):107-14doi: 10.2165/00044011-200525020-00003.
Lasseter, K. C., Porras, A. G., Denker, A., Santhanagopal, A., & Daifotis, A. (2005). Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates. Clinical drug investigation, 25(2), 107-14. https://doi.org/10.2165/00044011-200525020-00003
Lasseter, Kenneth C, et al. "Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates." Clinical drug investigation vol. 25,2 (2005): 107-14. doi: https://doi.org/10.2165/00044011-200525020-00003
Lasseter KC, Porras AG, Denker A, Santhanagopal A, Daifotis A. Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates. Clin Drug Investig. 2005;25(2):107-14. doi: 10.2165/00044011-200525020-00003. PMID: 17523760.
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Clin Drug Investig. 2005;25(2):107-14. doi: 10.2165/00044011-200525020-00003.

Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates.

Clinical drug investigation

Kenneth C Lasseter, Arturo G Porras, Andrew Denker, Anu Santhanagopal, Anastasia Daifotis

Affiliations

  1. Clinical Pharmacology Associates, Miami, Florida, USA.

PMID: 17523760 DOI: 10.2165/00044011-200525020-00003

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((1/2)gamma)) 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((1/2)gamma).

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((1/2)gamma) = -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((1/2)gamma) 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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