WHAT IS KNOWN AND OBJECTIVE: The assessment of bioequivalence of drugs intended for local action/targeted delivery and with poor systemic absorption presents unique challenges. Approaches such as pharmacodynamic (PD) bioequivalence testing have been proposed as alternatives to pharmacokinetic (PK) bioequivalence studies. Our objective is to comment on when PD bioequivalence testing might be considered appropriate and whether the acceptance criteria for bioequivalence could be adjusted based on observed variability in PD response. COMMENT: Pharmacokinetic bioequivalence studies are generally conducted to evaluate the rate and extent of drug absorption of a test drug as compared to a reference drug. However, this may not be appropriate for locally acting drugs, when the plasma drug concentrations, if measurable, are not correlated with the clinical therapeutic effect. Systemic absorption may in fact be undesirable for such drugs. The US Food and Drug Administration (FDA) recommends alternative approaches for evaluating the bioequivalence of acarbose, including a bioequivalence study with a PD endpoint. For the evaluation of therapeutic equivalence of highly variable drugs, adjusting the acceptance interval for the PK parameters has been discussed by the FDA and the European Medicines Agency (EMEA). However, it is still not clear whether the newly proposed methodology is applicable to PD bioequivalence testing. WHAT IS NEW AND CONCLUSION: Although no consensus has been reached on the criteria for PD bioequivalence testing, various approaches are currently being investigated. Further studies should be performed to assess whether an adjustment of the acceptance intervals is appropriate based on the within-subject variability of PD responses. This may potentially minimize the unnecessary exposure of a large number of subjects to the test drugs.
WHAT IS KNOWN AND OBJECTIVE: The assessment of bioequivalence of drugs intended for local action/targeted delivery and with poor systemic absorption presents unique challenges. Approaches such as pharmacodynamic (PD) bioequivalence testing have been proposed as alternatives to pharmacokinetic (PK) bioequivalence studies. Our objective is to comment on when PD bioequivalence testing might be considered appropriate and whether the acceptance criteria for bioequivalence could be adjusted based on observed variability in PD response. COMMENT: Pharmacokinetic bioequivalence studies are generally conducted to evaluate the rate and extent of drug absorption of a test drug as compared to a reference drug. However, this may not be appropriate for locally acting drugs, when the plasma drug concentrations, if measurable, are not correlated with the clinical therapeutic effect. Systemic absorption may in fact be undesirable for such drugs. The US Food and Drug Administration (FDA) recommends alternative approaches for evaluating the bioequivalence of acarbose, including a bioequivalence study with a PD endpoint. For the evaluation of therapeutic equivalence of highly variable drugs, adjusting the acceptance interval for the PK parameters has been discussed by the FDA and the European Medicines Agency (EMEA). However, it is still not clear whether the newly proposed methodology is applicable to PD bioequivalence testing. WHAT IS NEW AND CONCLUSION: Although no consensus has been reached on the criteria for PD bioequivalence testing, various approaches are currently being investigated. Further studies should be performed to assess whether an adjustment of the acceptance intervals is appropriate based on the within-subject variability of PD responses. This may potentially minimize the unnecessary exposure of a large number of subjects to the test drugs.