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Bioequivalence Studies in Drug Development
Methods and Applications
by Dieter Hauschke

Bioequivalence Studies in Drug Development focuses on the planning, conducting, analysing and reporting of bioequivalence studies, covering all aspects required by regulatory authorities.

Features:

  • Includes all the necessary pharmacokinetic background information
  • Presents parametric and nonparametric statistical techniques
  • Describes adequate methods for power and sample size determination
  • Includes appropriate presentation of results from bioequivalence studies
  • Provides a practical overview of the design and analysis of bioequivalence studies
  • Presents the recent developments in methodology, including population and individual bioequivalence
  • Reviews the regulatory guidelines for such studies, and the existing global discrepancies
  • Discusses the designs and analyses of drug-drug and food-drug interaction studies

Contents

Introduction

  • Bioavailability
  • Bioequivalence
  • Therapeutic equivalence
  • When are bioequivalence studies performed
  • Applications for products containing new active substances
  • Applications for products containing approved active substances
  • Applications for modified release forms essentially similar to a marketed modified release form
  • Design and conduct of bioequivalence studies
  • Crossover design and alternatives
  • Single vs. multiple dose studies
  • Pharmacokinetic characteristics
  • Subjects
  • Statistical models
  • Average bioequivalence
  • Population bioequivalence
  • Individual bioequivalence
  • Sample size
  • Aims and structure of the book

Metrics to characterize concentration-time profiles in single- and multiple-dose bioequivalence studies

  • Pharmacokinetic characteristics (metrics) for single-dose studies
  • Extent of bioavailability
  • Rate of bioavailability
  • Pharmacokinetic rate and extent characteristics (metrics) for multiple-dose studies

Basic statistical considerations

  • Additive and multiplicative model
  • The normal distribution
  • The lognormal distribution
  • Hypotheses testing
  • Consumer and producer risk
  • Types of hypotheses
  • Test for difference
  • Test for superiority
  • Test for noninferiority
  • Test for equivalence
  • Difference versus ratio of expected means
  • The normal distribution
  • The lognormal distribution
  • The RT/TR crossover design assuming an additive model.
  • Additive model and effects
  • Parametric analysis based on t-tests
  • Test for difference in carryover effects
  • Test for difference in formulation effects
  • Test for difference in period effects
  • Nonparametric analysis based on Wilcoxon rank sum tests
  • Test for difference in carryover effects
  • Test for difference in formulation effects
  • Test for difference in period effects

Assessment of average bioequivalence in the RT/TR design

  • The RT/TR crossover design assuming a multiplicative model
  • Multiplicative model and effects
  • Test problem
  • Estimation of the formulation difference
  • Test procedures for bioequivalence assessment
  • Analysis of variance
  • Example: Dose equivalence study
  • Two one-sided t-tests and (1-2a) 100% -confidence interval
  • Example: Dose equivalence study
  • Two one-sided Wilcoxon rank sum tests and (1-2a) 100%-confidence interval
  • Example: Dose equivalence study
  • Analysis of the characteristic time to maximum concentration
  • Bioequivalence ranges

Power and sample size determination for testing average bioequivalence in the RT/TR design

  • Challenging the classical approach
  • Exact power and sample size calculation
  • Modified acceptance ranges
  • Approximate formulas for sample size calculation
  • Exact power and sample size calculation by nQuery

Presentation of bioequivalence studies

  • Results from a single-dose study
  • Results from a multiple-dose study

Designs with more than two formulations

  • Williams designs
  • Example: Dose linearity study
  • Multiplicity
  • Joint decision rule
  • Multiple decision rule

Analysis of pharmacokinetic interactions

  • Pharmacokinetic drug-drug interaction studies
  • Absorption
  • Distribution
  • Elimination
  • Metabolism
  • Metabolic induction
  • Metabolic inhibition
  • Change of blood flow
  • Renal excretion
  • Hepatic/biliary excretion
  • Experimental design of in vivo drug-drug interaction studies
  • Examples to illustrate drug-drug interactions and the lack thereof
  • Pharmacokinetic characteristics for extent of absorption and clearance in drug-drug interaction studies
  • Theoretical background on AUC as a composite measure of absorption and clearance
  • Examples to illustrate the composite character of AUC
  • Recommendations for subsequent analyses
  • Pharmacokinetic food-drug interactions
  • Classification of food effects
  • Experimental design of food-drug interaction studies
  • Example: Theophylline food interaction study
  • Goal posts for drug interaction studies including no effect boundaries
  • Labeling

Population and individual bioequivalence

  • Brief history
  • Study designs and statistical models
  • Classical two-period, two-sequence crossover design
  • Replicate designs
  • Additive model
  • Basic concepts of aggregate measures
  • Example
  • Population bioequivalence
  • Moment-based criteria
  • Statistical procedures

Equivalence assessment in case of clinical endpoints

  • Design and testing procedure
  • Parallel group design
  • Crossover design
  • Power and sample size calculation
  • Parallel group design
  • Crossover design
  • Approximate formulas for sample size calculation
  • Exact power and sample size calculation by nQuery

Index

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Bioequivalence Studies in Drug Development
Methods and Applications
by Dieter Hauschke

2007 327 pages $109.00 + shipping
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