Assessing the bioequivalence of analogues of endogenous substances ('endogenous drugs'): considerations to optimize study design.
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.


OBJECTIVE
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.
Dissanayake
Sanjeeva
S
Medicines and Healthcare products Regulatory Agency, London, UK. sanjeeva.dissanayake@mhra.gsi.gov.uk
D005260:Female; D006801:Humans; D008297:Male; D010599:Pharmacokinetics; D011956:Receptors, Cell Surface / Q000187:drug effects*; D012107:Research Design; D013810:Therapeutic Equivalency
D011956:Receptors, Cell Surface