Article date: March 2010
By: Sanjeeva Dissanayake, in Volume 69, Issue 3, pages 238-244
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The complexities of assessing the bioequivalence of endogenous drugs are recognised.
• The FDA have published guidelines regarding the evaluation of levothyroxine and potassium chloride bioequivalence, whilst other authors have documented specific strategies to counter biases inherent in biostudies of endogenous drugs.
• A consolidated consideration of valid methods to optimise the design of such studies is however lacking.
WHAT THIS STUDY ADDS
• This paper is to the author's knowledge the first summarising various key approaches used to assess the bioequivalence of endogenous drugs, and to propose a series of recommendations for studies in this field.
BACKGROUND Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed.
AIMS To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs.
METHODS A literature search of the EMBASE and PubMed databases was performed.
RESULTS The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance‐deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra‐therapeutic drug doses.
CONCLUSIONS On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so‐called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed.
DOI: 10.1111/j.1365-2125.2009.03585.x
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