Document Type

Dissertation

Date of Degree

Fall 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Lee E. Kirsch

Abstract

Degradation product toxicity is a critical quality issue for a small group of useful drug products--e.g. lidocaine, isoniazid, chlorhexidine, gabapentin. In the traditional risk assessment approaches, a no-observed-adverse-effect level (NOAEL) derived from animal data is determined with the use of generic (and arbitrary) uncertainty factors to obtain an acceptable daily intake. The effects of compound-specific biological complexities and pharmacokinetics are typically not part of the risk calculations. The selection of uncertainty factors that account for interspecies or intraspecies difference concerning biokinetics and biodynamics has also generally failed to consider chemical-specific mechanism information or pharmacokinetics data. The use of combining in-vitro biopharmaceutical characterization methods and physiologically-based pharmacokinetic modeling has undergone extensive study and validation for predicting clinical drug blood level time profiles. The rationale for the proposed research is that a PBPK modeling utilizing rat to human scaling for target tissue toxicity in combination with the Monte Carlo method for estimating human target exposure distributions provides a rational basis for assessing drug stability safety issues for drug substances that potentially degrade to toxic compounds.

PBPK models for rats and humans were developed to simulate drug exposure time profiles after oral administration of model compounds including aniline, p-chloroaniline, 2,6-dimethylaniline, o-toluidine and p-aminophenol. The PBPK models were parameterized using a combination of literature values, computational models and standard in vitro experiments. Microsomal and hepatocyte metabolism studies were used to estimate the metabolic constants, and ultrafiltration was used to measure protein binding. Intestinal permeability was predicted using a set of related compound data to correlate measured Caco-2 permeability with molecular descriptors by multivariate regression. Sensitivity analyses were conducted to evaluate the impact of PBPK model parameters on plasma level predictions. To evaluate patient population effects on exposure profiles, the PBPK model parameters were varied in meaningful ways using Monte Carlo methods. Based on population PBPK models, distributions of target tissue exposure in rats and humans were simulated and compared to derive human safe dose.

As results, rat PBPK model-predicted aniline concentration time profiles were in reasonable agreement with published profiles. Distributions of target tissue exposure in rats and humans were generated and compared based on a criterion. A human reference dose was then selected at a value of 1% criteria. This approach was compared to traditional risk assessment calculations. In conclusion, the PBPK modeling approach resulted in drug degradation product risk specifications that were less stringent than those estimated by conventional risk assessment approach. The PBPK modeling approach provides a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

Public Abstract

Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug products (e.g. lidocaine, isoniazid, chlorhexidine, gabapentin). In recent years toxicity of unwanted components that remain with the active pharmaceutical ingredients, or arise during the manufacturing process and/or storage of the drug substance have received considerable attention industrial and regulatory scientists. Although the time course of potential toxic degradants in body will strongly affect product safety, these data are frequently unavailable in animal and impossible to safely obtain in human. The objective of this study is to incorporate the use of physiologically-based pharmacokinetic (PBPK) models in rats and humans for the development of rational degradant risk assessment procedures using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of literature values, computational methods and standard experiments. Microsomal and hepatocyte metabolism studies were used to estimate the metabolic constants, and ultrafiltration was used to measure protein binding. The impact of the uncertainties and variability in parameter values on model predictions were analyzed. Human safe doses for model compounds were selected based on the comparison between predicted rat target tissue exposure at critical dose and human exposure at a series of predetermined doses. This approach was compared to traditional risk assessment calculations.

In conclusion, the PBPK modeling approach provides a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

Keywords

publicabstract, Drug degradation, Physiologically based pharmacokinetic modeling, Risk assessment

Pages

xvi, 175 pages

Copyright

Copyright 2014 Quynh Hoa Nguyen

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