027: A Quantitative Evaluation of the Relationship Between Hepatic Extraction Ratio & Change in Plasma Half-Life Following Modulation of CYP3A Activity

Statement of Purpose, Innovation or Hypothesis: Hepatic extraction ratio (E_h,b) is the fraction of drug presented to the liver that is eliminated from blood during a single pass. Theoretically, equations derived from the well-stirred model for hepatic elimination indicate that clearance of drugs with high E_h,b is predominantly driven by hepatic blood flow, and their elimination half-life (T_1/2) is less impacted by metabolic enzyme expression levels [1]. On the other hand, clearance of drugs with low E_h,b is driven by the metabolic enzyme activity and unbound fraction in blood, and their T_1/2 is expected to change with changes in metabolic enzyme activity. An assessment of the relationship between E_h,b and change in T_1/2 (∆T_1/2) in the presence of strong CYP3A inhibition or induction can guide the study design of planned drug-drug interaction (DDI) studies.

Description of Methods & Materials: Focusing on FDA approved new molecular entities between 2020-2022 and internal Pfizer assets primarily metabolized by CYP3A, a publication search was conducted to build a database of drugs with complete information on total clearance, renal clearance, blood/plasma ratio, and T_1/2 data from DDI studies with strong CYP3A inhibitors or inducers. Subsequently, E_h,b for all drugs in the database was calculated. We sought to evaluate the relationship between E_h,b and ∆T_1/2 caused by strong CYP3A induction or inhibition.

Data & Results: A significant positive correlation (n = 16, Pearson’s correlation = 0.7, p-value < 0.05) was noted between E_h,b and ∆T_1/2 due to strong CYP3A induction. However, with strong CYP3A inhibition, a similar strong correlation between E_h,b and ∆T_1/2 was not seen (n = 19, Pearson’s correlation = -0.3, p-value > 0.1).

Interpretation, Conclusion or Significance: Despite a relatively small dataset (n = 16 – 19), this work validated the expectations from the well-stirred model in terms of the relationship between E_h,b and ∆T_1/2 due to strong CYP3A induction. It is worth noting that this correlation may be confounded for drugs that exhibit CYP3A autoregulation and/or produce metabolites that are also metabolized by CYP3A.

Disclosures: This work was sponsored by Pfizer; CT was an intern. The authors have no competing conflicts of interest to declare.

Citations/References: [1] Derendorf, H. and Schmidt, S. (2020) Rowland and Tozer’s Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 5^th edition.

Additional Information/Authors: Not applicable