Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions

Abstract

Drug transporters expressed in liver and kidney play a critical role in the elimination of a wide range of drugs and xenobiotics and inhibition of these transporters may therefore cause clinically significant drug-drug interactions (DDIs). Currently, in vitro transporter inhibition data are used to assess the risk that a drug candidate may act as an inhibitor of a transporter in patients at clinically relevant exposures. However, this approach is hampered by low confidence in in vitro to in vivo extrapolations, and large inter-system and inter-laboratory variability in in vitro data. Several endogenous compounds have been identified as substrates of drug transporters. Determining the impact of perpetrator drugs on the plasma or urinary exposure of these potential endogenous biomarkers in humans is being explored as an alternative approach to assess the DDI liability of drug candidates, especially in early drug development. In this review, we provide an overview of recently identified biomarkers used to study the inhibition of hepatic and renal transporters; summarize the methods and strategies employed to identify biomarkers; and discuss the utility, limitation, and future direction of biomarker approaches to predict transporter-mediated DDIs.

Effect of OATP1B1/1B3 Inhibitor GDC‐0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects

“…Recently, endogenous biomarkers of drug transporters have gained more interest from both industry and academia with a potential to replace or assist in prioritization of a dedicated DDI study and thus offering cost and time effectiveness. Multiple endogenous biomarkers of OATP1B1/1B3 have been suggested/proposed, including coproporphyrin I and III, conjugated and unconjugated bilirubin, conjugated metabolites of steroids, conjugated and unconjugated bile acids, fatty acid dicarboxylates tetradecanedioate and hexadecanedioate, thyroid hormones and their metabolites, and so on . Coproporphyrin I and III, which are porphyrin metabolites arising from heme synthesis, were recently reported to be the reasonable endogenous biomarkers correlating with OATP1B function .…”

“…Multiple endogenous biomarkers of OATP1B1/1B3 have been suggested/proposed, including coproporphyrin I and III, conjugated and unconjugated bilirubin, conjugated metabolites of steroids, conjugated and unconjugated bile acids, fatty acid dicarboxylates tetradecanedioate and hexadecanedioate, thyroid hormones and their metabolites, and so on. [16][17][18][19] Coproporphyrin I and III, which are porphyrin metabolites arising from heme synthesis, were recently reported to be the reasonable endogenous biomarkers correlating with OATP1B function. 18 A 5-to 6-fold increase in concentration of coproporphyrin I and III was observed after administration of rifampin (as a strong OATP1B inhibitor in humans), 18 suggesting their utility in capturing potent DDIs mediated by OATP1B1/1B3 inhibition.…”

Quantitative Prediction of OATP‐Mediated Drug‐Drug Interactions With Model‐Based Analysis of Endogenous Biomarker Kinetics

“…One of the important knowledge gaps in interpreting kinetic profiles of endogenous biomarkers is the involvement of other elimination pathways, such as other transporters or biotransformation. For CPI, MRP2 is likely involved in the elimination, as suggested from in vitro studies and altered kinetic profiles in patients with Dubin‐Johnson syndrome (genetically linked disease with MRP2 deficiency) or subjects with ABCC2 polymorphisms . It has implications on the inhibition potencies from clinical data.…”

“…For CPI, MRP2 is likely involved in the elimination, as suggested from in vitro studies 22,23 and altered kinetic profiles in patients with Dubin-Johnson syndrome (genetically linked disease with MRP2 deficiency) or subjects with ABCC2 polymorphisms. 24 It has implications on the inhibition potencies from clinical data. It is difficult, however, to quantify the contribution of MRP2 to overall elimination of CPI, because MRP2 is expressed in multiple organs, including the liver, kidneys, and intestines.…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…A recent study showed that CPI and CPIII can successfully predict strong and mild OATP1B‐mediated DDI in the clinic (Kunze, Ediage, Dillen, Monshouwer, & Snoeys, ). For detailed information on transporter biomarkers, please refer to other articles on the topic (Barnett et al, ; Chu et al, ; Chu, Chan, & Evers, ; Jones et al, ; Mariappan, Shen, & Marathe, ; Mueller, Sharma, Koenig, & Fromm, ; Rodrigues & Rowland, ; Shen, ; Yoshikado et al, ). Biomarkers are active research areas and future advances will help to provide new tools and insights to more accurately predict clinical DDIs.…”