Transcript Additional Considerations for BE studies

Additional
considerations
Saila Antila, PhD
WHO consultant
Training workshop on
Pharmaceutical Quality, Good
Manufacturing Practice &
Bioequivalence, Kiev 3.-7.10.2005
Bioequivalence based
on the metabolite
Reasons:
 pro-drug
 analytical difficulties in determination
of the parent drug
 concentration of the active
substance is too low
 drug unstable in the biological
matrix
 short half-life of the parent drug
Bioequivalence based
on the metabolite
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if the metabolite contributes to the
activity of the drug, the bioequivalence
of the metabolite should be determined
if the pharmacokinetics of the drug is
non-linear, both parent drug and
metabolite should be measured
Bioequivalence based
on the metabolite
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In bioequivalence studies measurement of
the parent drug is generally recommended
concentration-time profile of the parent drug
is more sensitive to changes in formulation
performance
metabolite is more reflective of metabolite
formation, distribution and elimination
measurement of inactive metabolite can be
rarely justified
Bioequivalence based
on the metabolite
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bioequivalence should be analysed
using confidence interval approach
the metabolite data can be used to
provide supportive evidence of
comparable therapeutic outcome
Stereochemistry and
bioanalytics
WHO
 a non-stereoselective assay is currently
acceptable for most pharmacokinetic
bioequivalence studies
 Stereoselective assay when
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enantiomers have different
pharmacological or metabolic profile
systemic availability non-linear
Stereochemistry and
bioanalytics
Product containing chiral active
substances should be based upon
enantiomeric bioanalytical methods
unless (EMEA):
 both products contain the same
stable single enantiomer
 both products contain the racemate
and both enantiomers show linear
pharmacokinetics
Stereochemistry and
bioanalytics
FDA: Measurement of of individual
enantiomers is recommended
only if
 the enantiomers exhibit different
pharmacodynamic characteristics
 the enantiomers exhibit different
pharmacokinetic characteristics
continues
Stereochemistry and
bioanalytics (continues)
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primary efficacy and safety resides with
the minor enantiomer
nonlinear absorption is present
Urine data
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urine excretion data may be
advantageous in determining the
extend of drug input in case the drug
is excreted predominately renally
if concentrations in blood are too
small to be detected and over 40 %
of the drug is eliminated unchanged
in urine, then urine may serve as the
biological fluid to be sampled
Urine data
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if urine excretion rate is measured, the
product determined should represent a major
fraction of the dose
not a good measure to describe absorption
Urine data
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sampling points or periods should be carefully
chosen (at least 7-10 biological half-lives)
Sampling points for example: 0-2, 2-4, 4-8, 812, 12-24 hours
Ae =Cu x V
Ae= cumulative amount excreted
Cu = drug concentration in urine
V = urine volume
Excretion rate = dAe/dt