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Additional considerations

Additional considerations. Saila Antila, PhD WHO consultant. 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

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Additional considerations

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  1. Additional considerations Saila Antila, PhD WHO consultant Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev 3.-7.10.2005

  2. 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

  3. Bioequivalence based on the metabolite • 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

  4. Bioequivalence based on the metabolite • 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

  5. Bioequivalence based on the metabolite • bioequivalence should be analysed using confidence interval approach • the metabolite data can be used to provide supportive evidence of comparable therapeutic outcome

  6. Stereochemistry and bioanalytics WHO • a non-stereoselective assay is currently acceptable for most pharmacokinetic bioequivalence studies • Stereoselective assay when • enantiomers have different pharmacological or metabolic profile • systemic availability non-linear

  7. 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

  8. 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

  9. Stereochemistry and bioanalytics (continues) • primary efficacy and safety resides with the minor enantiomer • nonlinear absorption is present

  10. Urine data • 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

  11. Urine data • if urine excretion rate is measured, the product determined should represent a major fraction of the dose • not a good measure to describe absorption

  12. Urine data • 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, 8-12, 12-24 hours • Ae =Cu x V • Ae= cumulative amount excreted • Cu = drug concentration in urine • V = urine volume • Excretion rate = dAe/dt

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