HUSCAP logo Hokkaido Univ. logo

Hokkaido University Collection of Scholarly and Academic Papers >
Global Institution for Collaborative Research and Education : GI-CoRE >
Peer-reviewed Journal Articles, etc >

Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

This item is licensed under:Creative Commons Attribution-NonCommercial 4.0 International

Files in This Item:
kfy035.pdf974.8 kBPDFView/Open
Please use this identifier to cite or link to this item:

Title: Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)
Authors: Convertino, Matteo Browse this author
Church, Timothy R Browse this author
Olsen, Geary W Browse this author
Liu, Yang Browse this author
Doyle, Eddie Browse this author
Elcombe, Clifford R Browse this author
Barnett, Anna L Browse this author
Samuel, Leslie M Browse this author
MacPherson, Iain R Browse this author
Evans, Thomas R J Browse this author
Keywords: APFO
phase 1 trial
PK/PD modeling
Issue Date: May-2018
Publisher: Oxford University Press
Journal Title: Toxicological sciences : an official journal of the Society of Toxicology
Volume: 163
Issue: 1
Start Page: 293
End Page: 306
Publisher DOI: 10.1093/toxsci/kfy035
PMID: 29462473
Abstract: A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50-1200 mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately -1.2×10-3 mmol/l/μM and 2.8×10-3 pmol/l/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175 000-230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiologic studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects.
Type: article
Appears in Collections:国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: Matteo Convertino

Export metadata:

OAI-PMH ( junii2 , jpcoar_1.0 )

MathJax is now OFF:


 - Hokkaido University