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A RATIONAL PHARMACOKINETIC MODEL FOR PREDICTING
OSTEONECROSIS OF THE JAWS RELATED TO
ALENDRONATE AND PAMIDRONATE
by
Allan C. Jones
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(PHARMACEUTICAL SCIENCES)
August 2011
Copyright 2011 Allan C. Jones
Object Description
| Title | A rational pharmacokinetic model for predicting osteonecrosis of the jaws related to alendronate and pamidronate |
| Author | Jones, Allan C. |
| Author email | acjdds@mac.com;acjdds@mac.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2011-06-30 |
| Date submitted | 2011-08-01 |
| Date approved | 2011-08-01 |
| Restricted until | 2011-08-01 |
| Date published | 2011-08-01 |
| Advisor (committee chair) | Okamoto, Curtis T. |
| Advisor (committee member) |
Jelliffe, Roger Neely, Michael J. Hamm-Alvarez, Sarah F. |
| Abstract | Alendronate is the most frequently prescribed drug for the treatment and prevention of low bone mineral density worldwide. It is nearly identical to pamidronate, the first aminobisphosphonate used for therapeutic inhibition of bone resorption. Approved in 1991, pamidronate has become widely used as an intravenous drug for treatment of metastatic lesions of cancer in bone since 2000. In 2003, osteonecrosis of the jaws was discovered to occur in cancer patients treated with pamidronate and, to a much lesser degree, those who were treated with oral alendronate for osteopenia and osteoporosis. The necrotic lesions of the jaws occurred in dental patients who had undergone surgery. This malady is now commonly described as bisphosphonate-related osteonecrosis of the jaws. ❧ There is controversy in the dental profession regarding the route of administration in the pathogenesis of this disease. Organized dentistry, with no rational basis, has promulgated the opinion that alendronate, though nearly identical in all manner of pharmacological behavior, carries less risk for causing osteonecrosis. It is the opinion of two prominent dental organizations that there is no risk of osteonecrosis for patients undergoing oral surgical procedures for the first three years of therapy with oral alendronate. ❧ A recent USC School of Dentistry study disagrees. Here it was discovered that surgery patients were at risk for this disease within one year of initiated oral therapy with alendronate. This study shows that oral bisphosphonates do indeed pose the same risk as intravenous bisphosphonates. ❧ Intravenous pamidronate and oral alendronate differ only in the dosing and rate of accumulation in the skeleton. This thesis is a rational attempt to quantify the time required for oral pamidronate and, by analogy oral alendronate, to reach the toxic threshold for induction of osteonecrosis. This threshold was recently proposed through in vitro methodology by Landesberg et al. ❧ Serge Cremers, the Dutch pharmacokinetics expert, developed a model in 2002 for bisphosphonate accumulation in bone that comingled data for alendronate. He reasoned, as we do in this study, that the molecular features of the two drugs would confer similar pharmacokinetic characteristics. The urine and serum data from this study were provided to the Laboratory of Applied Pharmacokinetic (LAPK), Keck School of Medicine of USC. This allowed for the creation of a new model of pamidronate accumulation in skeletal tissues with nonparametric adaptive grid software (NPAG), LAPK’s Bayesian approach to nonparametric pharmacokinetic studies. As a coauthor with Landesberg et al, Cremers and his colleagues established an in vitro threshold for toxicity to keratinocyte migration that defines the most plausible mechanism to date for bisphosphonate-related osteonecrosis of the jaws. Specifically, they determined a threshold concentration for pamidronate in solution wherein cellular migration essential to healing is completely inhibited without apoptosis. LAPK determined the concentration of accumulated oral pamidronate and alendronate in skeletal tissues required to reach this threshold when liberated by osteoclastic resorption. ❧ A novel factor in the LAPK model is the use of total bone mineral content as a parameter for quantifying individual differences in the rate of accumulated concentration of alendronate and pamidronate. For the first time it is shown mathematically that with current fixed regimes of alendronate, those with less total bone mass will reach toxic levels more quickly. ❧ The last simulation investigated the effect of impaired kidney function. With renal clearance reduced by 50%, no significant change in the rate of accumulation was predicted. Reduced renal clearance does not enhance the accumulation of oral bisphosphonate in bone mineral. |
| Keyword | bisphosphonate; osteonecrosis; alendronate; pamidronate; Bayesian; pharmacokinetic |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Jones, Allan C. |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-JonesAllan-221.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | A RATIONAL PHARMACOKINETIC MODEL FOR PREDICTING OSTEONECROSIS OF THE JAWS RELATED TO ALENDRONATE AND PAMIDRONATE by Allan C. Jones A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (PHARMACEUTICAL SCIENCES) August 2011 Copyright 2011 Allan C. Jones |
