Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug‐Drug Interaction Evaluation: Perspectives From the International Transporter Consortium

Abstract

on behalf of the International Transporter ConsortiumDrug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic (PK) drug-drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transportermediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state-of-the-art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.Drug transporters can modulate the absorption, distribution, metabolism, and excretion (ADME) of substrate drugs and endogenous substances, ultimately determining their exposure in systemic circulation and tissues. 1 Transporter substrate or modulator (inhibitor or inducer) drugs can become clinical victims or perpetrators of drug-drug interactions (DDIs), respectively, when the transporter in question is a substantial contributor to the pharmacokinetics (PK) of the victim drug and can be inhibited or induced in the clinical setting. For example, lapatinib, a P-glycoprotein (P-gp) inhibitor, increased digoxin exposure by 2.8-fold (TYKERB labeling at Drugs@FDA), whereas tipranavir/ ritonavir, a P-gp inducer, decreased saquinavir/ritonavir exposure by 76% (APTIVUS labeling at Drugs@FDA). Understanding DDIs is an integral part of risk assessment in drug development considering the common practice of concomitant use of multiple medications. 1-3

Positron Emission Tomography Imaging of [11C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A

“…Therefore, in the RSV‐RIF study, RIF likely affected the first‐pass hepatic extraction of RSV resulting in a bigger increase in RSV plasma concentration. The percent change in plasma concentrations of CPI, CPIII, TBILI, and DBILI in our study are comparable to those observed in humans following RIF administration and cynomolgus monkeys after CsA administration (100 mg/kg p.o.) .…”

“…Therefore, in the RSV-RIF study, RIF likely affected the firstpass hepatic extraction of RSV resulting in a bigger increase in RSV plasma concentration. The percent change in plasma concentrations of CPI, CPIII, TBILI, and DBILI in our study are comparable to those observed in humans following RIF administration [35][36][37] and cynomolgus monkeys after CsA administration (100 mg/kg p.o.). 38 These percent changes are greater for the biomarkers than those for blood [ 11 C]RSV AUC 0-30 minutes because the biomarkers likely have greater fraction transported via OATPs than RSV (which is a substrate of both OATPs and NTCP).…”

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

“…In the transporter field, great progress has been made to identify clinical relevant biomarkers as substrates for various transporters, such as CPI (coproporphyrin I) and CPIII (coproporphyrin III) for the OATPs, creatinine and N 1 ‐methylnicotinamide for OCT2/MATE, and taurine for OAT1 (Chu et al, ). Several transporter biomarkers appear to be more sensitive and robust than the enzyme biomarkers in the clinic.…”

Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

“…Transporters with only mRNA or limited data are depicted in brown circles, whereas those that have both gene expression and protein abundance data are depicted in green circles. (Adapted/modified from Brouwer et al and Chu et al …”

“…Transporters with only mRNA or limited data are depicted in brown circles, whereas those that have both gene expression and protein abundance data are depicted in green circles. (Adapted/modified from Brouwer et al14 and Chu et al67 ) Noteworthy, the localization of OATP2B1 remains questionable. Future investigation is needed to ascertain if its localization is subject to developmental changes.…”