Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective

Abstract

Bile salt export pump (BSEP) inhibition has emerged as an important mechanism that may contribute to the initiation of human drug‐induced liver injury (DILI). Proactive evaluation and understanding of BSEP inhibition is recommended in drug discovery and development to aid internal decision making on DILI risk. BSEP inhibition can be quantified using in vitro assays. When interpreting assay data, it is important to consider in vivo drug exposure. Currently, this can be undertaken most effectively by consideration of total plasma steady state drug concentrations (Css,plasma). However, because total drug concentrations are not predictive of pharmacological effect, the relationship between total exposure and BSEP inhibition is not causal. Various follow‐up studies can aid interpretation of in vitro BSEP inhibition data and may be undertaken on a case‐by‐case basis. BSEP inhibition is one of several mechanisms by which drugs may cause DILI, therefore, it should be considered alongside other mechanisms when evaluating possible DILI risk.

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

“…Morgan et al . has shown with a larger collection of marketed drugs that a ratio of a drug's total systemic steady‐state exposure to BSEP IC 50 value >0.1x highlights an enhanced risk area associated with human DILI …”

“…The uniqueness of this work is based on examining the availability of some clinical samples to corroborate the mechanistic work conducted in vitro. A recent clinical review article on behalf of the International Transporter Consortium suggests that an exposure margin approach, not intrinsic potency of BSEP, is needed to understand the potential hepatotoxicity liability of a drug in development, a recommendation borne out by examination of this small clinical study only made possible by access to clinical samples. This incident prompted the addition of standardized language in early clinical protocols to collect, retain and examine serum samples, leftover from the conduct of safety labs, for exploratory safety biomarker work in with subject consent in advance of the clinical trial start.…”

“…The uniqueness of this work is based on examining the availability of some clinical samples to corroborate the mechanistic work conducted in vitro. A recent clinical review article on behalf of the International Transporter Consortium suggests that an exposure margin approach, not intrinsic potency of BSEP, is needed to understand the potential hepatotoxicity liability of a drug in development, 41 a recommendation borne out by ALEO ET AL. examination of this small clinical study only made possible by access to clinical samples.…”

The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation

“…Finally, it has recently been proposed that if the IC 50 for inhibition of the BSEP is > 25 μM, bile acid accumulation can be generally excluded as a relevant mechanism . This is probably the case with most drugs and where oxidative stress and mitochondrial impairment are not involved.…”

“…16 Finally, it has recently been proposed that if the IC 50 for inhibition of the BSEP is > 25 μM, bile acid accumulation can be generally excluded as a relevant mechanism. 24 This is probably the case with most drugs and where oxidative stress and mitochondrial impairment are not involved. However, DILIsym modeling has shown with certain drugs and metabolites with BSEP IC 50 values > 25 μM, bile acid accumulation can still contribute significantly to toxicity if one or both of the other mechanisms are operative.…”