Mathematical Modelling of Chronic Drug Infusion for Toxicity Assessment

A problem presented at the UK MMSG NC3Rs Study Group 2013.

Presented by:
Miss Áine Norton (Molecular and Clinical Pharmacology, University of Liverpool)
Dr Jean Sathish (Molecular and Clinical Pharmacology, University of Liverpool)
Dr Dominic Williams (Department of Molecular and Clinical Pharmacology, University of Liverpool)
Participants:
L Aarons, KA Beattie, RO Eljazi, AM Norton, NC Pearson, KR Rajoli, DM Reddyhoff, G Sathish, Marco Siccardi, D Webb, DP Williams

Problem Description

Adverse drug reactions are a major public health problem. Toxicity issues account for ~21% drug attrition during drug development and current safety testing strategies require considerable animal use. A mechanistic understanding of the molecular and cellular events that culminate in whole organ toxicity underpins development of novel drug safety assessment strategies.

Current models for safety testing are limited by intrinsic differences between animal and man with respect to how drug levels in the blood are maintained. Specifically, the rapid in vivo elimination of drugs in rodents results in qualitative and quantitative differences in pharmaco-toxicological endpoints and confounds comparisons to the human setting.

Chronic longitudinal analysis allows the generation of before-during-after type of data sets and can give valuable information such as:

  1. The steady state pharmacokinetics of the drug – reflecting the clinical situation
  2. Side-step drug holiday issues in animal models on daily dosing regimes
  3. The appearance and time course of clinically relevant parameters
  4. Biomarker identification and validation
  5. Dynamic changes in combinations of biomarkers and association patterns
  6. Identification of transition points or switch between pathological states – eg apoptosis to necrosis
  7. Reduction of experimental variation and increase in experimental power

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Study Group Report

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