BABE Studies & The Importance Of Metabolite Data
Sponsors conduct bioavailability testing to assess and establish pharmacokinetic parameters. These parameters include the rate and extent of absorption, metabolism and elimination half-life, rate of excretion, ADME properties after single and multiple doses, and much more. These specifications are crucial in designing dosage regimens. On the other hand, bioequivalence testing assesses the in vivo biological equivalence between a test drug and a reference-listed drug. When two drugs are bioequivalent, they are expected to be similar for all purposes. Hence, bioavailability and bioequivalence (BA/BE) studies are integral to different stages of drug development.
Similar to pharmacokinetics, toxicokinetic processes evaluate drug toxicity data. Pharmacokinetics parameters help researchers understand the drug and metabolite concentration in the plasma and their effects relative to the time and route of administration. Toxicokinetic parameters employ identical Cmax, and AUC approaches to assess drug toxicity in terms of its ADME properties. Hence, toxicokinetic studies are crucial for evaluating drug toxicity with respect to the time and course of drug action.
Importance of metabolite data
Generally, bioequivalence analysis is more popular as they are inexpensive compared to clinical trials. Bioequivalence evaluations depend on the average bioequivalence between two drug products. Most often, bioequivalence is conducted focusing on the parent drug, even when the role of metabolites is hugely debated. The primary reason for the focus on the parent drug during bioequivalence studies is that the concentration-time profile of a parent drug is more sensitive to variation in performance than its metabolite.
When the parent drug is the only active substance in the product or when it is not metabolized, sponsors can consider the parent drug during bioequivalence analysis. However, there are circumstances when both parent drugs and metabolites must be analyzed. These situations include:
- Low levels of parent drug in biological fluids
- Unstable parent drug in the matrix of interest
- Inactive parent drug
- Rapid formation of metabolite
- Metabolite has a significant impact on the net activity.
The US FDA guidance recommends measuring the parent drug during bioequivalence analysis. Again, the rationale behind these guidelines is that the parent drug is more prone to changes in performance compared to the metabolite. However, the guidance recommends measuring metabolites when the gut wall or presystemic metabolism results in metabolite formation or when the metabolite may affect the efficacy and safety of the drug product. In all other situations, FDA recommends measuring only the parent drug during bioequivalence testing.
During measuring the metabolite in bioequivalence analysis, the 90% interval must be applied separately to the parent drug and the metabolite. This individual analysis is crucial as the pharmacokinetics properties of the parent drug and metabolite may differ. Recent trends in BA/BE studies suggest that metabolite pharmacokinetic data is increasingly employed in bioequivalence assessments and bioavailability studies. This trend can be due to the impact of metabolite data in designing appropriate pharmacokinetic studies and optimizing intrasubject variability data.
Hence, researchers must revisit the importance of metabolite data and consider the factors impacting intra-subject variability, which may directly affect the design and conduct of bioequivalence clinical trials.