LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416

LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416

Bibliographic Details
Main Author: Zhu, Yao-Wei
Language:English
Published: University of Cincinnati / OhioLINK 2001
Subjects:
paclitaxel
SU5416
Limited Sampling Model
Pharmacokinetics
AUC
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin984580545
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin9845805452021-08-03T06:16:02Z LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416 Zhu, Yao-Wei paclitaxel SU5416 Limited Sampling Model Pharmacokinetics AUC Area under the plasma concentration-time curve (AUC) is one of the key pharmacokinetic (PK) parameters essential in evaluating the pharmacodynamics and toxicodynamics, drug-interactions and inter-day or inter-cycle variability of anti-cancer agents during phase II/III trials, and eventually for therapeutic drug monitoring. Conventional PK studies require frequent and extensive blood sampling for AUC estimation. For many reasons, ethical, technical and economical, it is difficult to conduct such studies. Therefore, it is desirable to develop statistically validated Limited Sampling Models (LSMs) that facilitate AUC determination using only few (1-3) blood samples. In this study, PK of paclitaxel, a widely used anti-mitotic agent (225 mg/m <sup>2</sup> I.V. over 3 hrs, n = 21), and SU5416, an investigational anti-angiogenic compound (4.4 - 145 mg/m <sup>2</sup> I.V. over 10 - 70 min, n = 63), was conducted as a part of several Phase I-III trials. Multiple linear regression analyses between AUC and selected plasma concentrations were performed. Various LSMs (1 to 3 concentrations versus AUC) were developed from randomly selected subjects (Training, paclitaxel n = 14; SU5416 n = 42). The remaining subjects were used for testing the bias (percentage mean prediction error, MPE%) and precision (percentage root-mean-squared prediction error, RMSE%) of the equations (Validation, paclitaxel n = 7; SU5416 n = 21). The optimum LSMs were identified by comparing mean MPE% and RMSE% of 10-12 bootstraps across equations. The LSM chosen for paclitaxel utilized only three plasma concentrations: AUC (µg·ml <sup>-1</sup> ·h) = 3.18·C <sub>1HR</sub> + 2.63·C <sub>3HR</sub> + 48.34·C <sub>24HR</sub> - 4.3 (MPE% = 1.7 +/- 10.1%, RMSE% = 18.4 +/- 5.7%). This model was further validated in subjects involved in a study, where paclitaxel (170 mg/m <sup>2</sup> I.V. over 3 hrs) was given in combination with amifostine. The LSM chosen for SU5416 utilized two plasma levels: lnAUC (ng·mL <sup>-1</sup> ·hr) = 0.160·lnDose + 0.281·lnINFT + 0.613·lnC <sub>20MIN</sub> + 0.216·lnC <sub>2HR</sub> + 0.578 (MPE% = 1.0 +/- 4.8%, RMSE% = 16.5 +/- 3.3%). This model was further validated employing data from Day 25 of SU5416 dosing. The potential use of these models for evaluating drug-drug interactions and inter-day variability in drug clearance was demonstrated, which underscores the significance of the models in clinical drug development. 2001-10-11 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin984580545 http://rave.ohiolink.edu/etdc/view?acc_num=ucin984580545 restricted--full text not available online This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic paclitaxel
SU5416
Limited Sampling Model
Pharmacokinetics
AUC
spellingShingle paclitaxel
SU5416
Limited Sampling Model
Pharmacokinetics
AUC
Zhu, Yao-Wei
LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416
author Zhu, Yao-Wei
author_facet Zhu, Yao-Wei
author_sort Zhu, Yao-Wei
title LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416
title_short LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416
title_full LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416
title_fullStr LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416
title_full_unstemmed LIMITED SAMPLING STRATEGIES FOR FACILE DETERMINATION OF THE AREA UNDER THE CURVE OF ANTI-CANCER AGENTS, PACLITAXEL AND SU5416
title_sort limited sampling strategies for facile determination of the area under the curve of anti-cancer agents, paclitaxel and su5416
publisher University of Cincinnati / OhioLINK
publishDate 2001
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin984580545
work_keys_str_mv AT zhuyaowei limitedsamplingstrategiesforfaciledeterminationoftheareaunderthecurveofanticanceragentspaclitaxelandsu5416
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