Biomarkers for In Vivo Assessment of Transporter Function

Abstract

Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed.

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

“…DMD Fast Forward. Published on May 18, 2018as DOI: 10.1124 at ASPET Journals on April 1, 2019 dmd.aspetjournals.org Downloaded from endogenous clinical biomarkers of OATP1B, including identification and validation of these biomarkers, has been exponentially increasing in the last few years (Chu et al, 2017, Mariappan et al, 2017, Rodrigues et al, 2017, Muller et al, 2018.…”

Comprehensive Evaluation of the Utility of 20 Endogenous Molecules as Biomarkers of OATP1B Inhibition Compared with Rosuvastatin and Coproporphyrin I

“…biomarkers in the presence of OATP1B inhibitors; these studies have been done in preclinical species (Chu et al, 2015;Watanabe et al, 2015;Shen et al, 2016;Thakare et al, 2017) and in humans (Lai et al, 2016;Shen et al, 2017Shen et al, , 2018Takehara et al, 2017Takehara et al, , 2018Kunze et al, 2018;Liu et al, 2018). Selectivity, sensitivity, and minimal variability in the baseline condition need to be considered for evaluation of endogenous molecules as potential clinical biomarkers of transporter function in vivo (Chu et al, 2017;Chu et al, 2018;Müller et al, 2018;Rodrigues et al, 2018). However, interpretation of endogenous biomarker interaction (EBI) data can be challenging due to other occurring physiologic processes usually not considered with clinical probes, such as synthesis, postprandial release, and diurnal rhythm (Rodrigues et al, 2018).…”

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

“…As a result, investigators have turned their attention to various circulating endogenous compounds as potential OATP1B biomarkers. It is envisioned that such biomarkers could facilitate OATP1B DDI risk assessment early in phase I with the potential to circumvent the need for formal DDI studies involving probe drug administration . Furthermore, there is potential to evaluate DDI risk in special subject populations (e.g., diseased, pregnancy, elderly, and pediatric).…”