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 (C_ss,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.

Figure 1

Localization of hepatic bile acid and lipid transporters. ATP8B1, ATPase aminophospholipid transporter 8B1; BA, bile acids; BSEP, bile salt export pump; MDR3, multidrug resistance protein 3; MRP, multidrug resistance protein; NTCP, Na⁺‐taurocholate co‐transporting polypeptide; OATP, organic anion transporting polypeptide; OST, organic solute transporter; PC, phosphatidylcholine; PS, phosphatidylserine. Red, ATP binding cassette (ABC) transporters; green, P‐type ATPase; purple, solute carrier (SLC) transporters.

Figure 2

Proposed role of bile salt export pump (BSEP) inhibition in drug‐induced liver injury. *Adaptation may arise via upregulation of BSEP expression and upregulation or downregulation of other hepatic plasma membrane efflux or uptake transporters, respectively, plus intracellular mechanisms that include farnesoid X receptor (FXR)‐mediated downregulation of bile acid synthesis (see text for details).

Figure 3

Potential guided workflow to interpret and mitigate bile salt export pump (BSEP) inhibition in drug discovery and/or early clinical development (phase I/II). The workflow is based on current knowledge and could be considered when making internal decisions on potential BSEP liabilities. The science has not evolved to a point where a standardized decision tree can be constructed and used by regulators due to gaps in our knowledge. (i) *The suggested cutoff values are based on limited published data and are intended to help focus additional discussion. Further research/justification is needed to reach final consensus on the feasibility of the suggested approaches. Typical assay conditions are summarized in Table  1 . (ii) In the absence of clinical data, total concentration estimates may be from preclinical efficacy models or from other early predictions of human pharmacokinetics. Total plasma steady state drug concentrations (C_ss,plasma) correlation to BSEP concentration of half inhibition (IC ₅₀) should be revisited when relevant clinical data are available. When total C_ss,plasma is not known, estimated or determined total peak plasma concentration (C_max) data may be used instead. (iii) Higher likelihood of drug‐induced liver injury (DILI) is expected if one or more DILI liabilities are flagged along with BSEP inhibition. (iv) Refer to Figure 3 and the article for discussion follow‐up studies and recommendations. (v) In clinical phase IIB/III studies, the strategy moves to considering metabolites and testing other transporters, in order to provide more comprehensive characterization of the drug prior to registration and labeling.

Figure 4

Follow‐up studies that can be used to provide additional insight into the potential clinical relevance of bile salt export pump (BSEP) inhibition. (i) Refer to the article for discussion of follow‐up studies and recommendations. (ii) To date, assays for organic solute transporter (OST)alpha and beta inhibition are not commercially available. CL, clearance; DILI, drug‐induced liver injury; MRP, multidrug resistance‐associated protein; NTCP, Na+‐taurocholate co‐transporting polypeptide; OATP, organic anion transporting polypeptide.