Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation
Perspectives From the International Transporter Consortium
Transporter studies are performed at various stages of drug development ‒ discovery to first-in-human (FIH) phase (in-vitro substrate and inhibition studies), FIH to proof of concept (POC) phase (clinical DDIs), and POC to new drug application (NDA)/post-marketing phase (product labeling and post-marketing surveillance). Currently, in-vitro transporter inhibition assays are conducted to determine the risk for potential clinical DDIs.
During clinical DDI studies, an appropriate probe substrate is selected to tease out the effect of NME inhibition of a transporter, to understand the mechanism of the DDI, and enable extrapolation to other drugs, leading to appropriate product labeling. Due to multiple factors, including the limitations of IVIVE, an overlap of substrate/inhibition for enzymes and transporters, multiple drug binding sites on transporters, and the fact that organ-specific changes in drug exposure may not be reflected in systemic PK, this strategy may result in false-positive and false-negative outcomes.
Instead of using a drug as a clinical probe substrate, a validated endogenous biomarker offers the potential for evaluating NMEs as transporter inhibitors in early clinical studies (by reanalyzing already-collected PK samples), without the need for dedicated clinical DDI studies. A list of desirable characteristics for biomarkers for this purpose are summarized in Table 1.
Based on the above characteristics and data generated so far, ITC has compiled a list of suitable probe substrates and biomarkers to study transporter-related clinical DDIs (Table 2).
Biomarkers listed in the above table are additionally transported by MRP2 and MRP3 (CPI, CPIII, CB), OATP2B1 (CPIII), OAT1 (HDA, TDA), OAT3 (GCDCA-S, HAD, TDA) or NTCP (GCDCA-S), thus reducing their selectivity.
As a perpetrator drug may inhibit multiple transporters, a probe drug cocktail approach has been tested in vitro and in clinics. Examples of cocktails successfully tested are shown in Table 3.
- ITC proposed the following workflow for the identification, characterization, and validation of an endogenous biomarker
- ITC proposed the following decision tree for incorporating endogenous biomarkers and probe drugs to assess transporter-related inhibition during drug development
- Chu X, Liao M, Shen H, Yoshida K, Zur AA, Arya V, Galetin A, Giacomini KM, Hanna I, Kusuhara H, Lai Y, Rodrigues D, Sugiyama Y, Zamek-Gliszczynski MJ, Zhang L; International Transporter Consortium. Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium. Clin Pharmacol Ther.2018, 104(5):836-864
- Müller F, Sharma A, König J, Fromm MF. Biomarkers for in vivo assessment of transporter function. Pharmacol Rev. 2018, 70(2): 246-277
- Webinar presented by Dr. Zamek-Gliszczynski, Senior Fellow and Director, DMPK, GlaxoSmithKline https://www.absorption.com/kc/webinar-state-of-the-art-in-clinical-transporter-ddi-evaluation/
- Absorption Systems’ Transporter Reference Guide, 2018, 4th Edition, Absorption Systems https://www.absorption.com/kc/transporter-reference-guide-4th-edition-download/