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The following message was posted to: PharmPK
Occasionally bioequivalence studies are performed using a supra-therapeutic
dose, mainly justified by the absence of an adequate bio-assay for the
concentrations expected under therapeutic doses. For the same reason dose
proportionality is established in a supra-therapeutic dose range only, and
is extrapolated to lower doses. This extrapolation is not completely
correct, there might be deviations from proportionality in the range of low
doses, at least theoretically.
I don't know what is more frequent:
1) Authorities accepted the approach above
2) Authorities rejected the approach above (the arguments would be
Can anybody help with some examples?
With kind regards,
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EMEA Regulatory Agency accepts Bioequivalence studies with supra-therapeutic doses for Endogenous drugs.
Administration of supra-therapeutic doses can be considered in bioequivalence studies of endogenous drugs, provided that the dose is well tolerated, so that the additional concentrations over baseline provided by the treatment may be reliably determined.
In the rare situation where problems of sensitivity of the analytical method preclude sufficiently precise plasma concentration measurements after single dose administration and where the concentrations at steady state are sufficiently high to be reliably measured, a multiple dose study may be acceptable as an alternative to the single dose study. However, given that a multiple dose study is less sensitive in detecting differences in Cmax, this will only be acceptable if the applicant can adequately justify that the sensitivity of the analytical method cannot be improved and that it is not possible to reliably measure the parent compound after single dose administration taking into account also the option of using a supra-therapeutic dose in the bioequivalence study.
Please find an article on Bioequivalence study conducted with Supra-therapeutic dose in the following link
Johan Rosenborg, Per Larsson, and Lars Nyberg. Pharmacokinetics of bambuterol during oral administration of plain tablets and solution to healthy adults. Br J Clin Pharmacol. 2000 March; 49(3): 199-206.
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