Pharmacokinetic Drug-Drug Interaction Study to Identify Biomarkers of Kidney Transporters
Condition: Interaction; Endogenous Biomarkers
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The objective of this study is to confirm the feasibility of using a panel of endogenous
      substrates/metabolites as a robust biomarker of OCTs and OATs by conducting a controlled,
      comprehensive clinical drug-drug interaction study in healthy adult volunteers. Metformin and
      furosemide will be used as probe drugs for OCTs and OATs, respectively; cimetidine and
      probenecid will be used as corresponding inhibitors. Results from this study will validate
      this novel approach, which will be extended to children by collaborators at Children's Mercy
      Hospital in Kansas City, MO.
    

Detailed description: 
      The kidneys are major organs responsible for the excretion of both endogenous and exogenous
      compounds, the latter including drugs and other xenobiotics. Excretion occurs via passive or
      active processes, the latter involving transporters such as organic cation transporters
      (OCTs) and organic anion transporters (OATs). Inhibition of these transporters, coupled with
      the large interindividual variability in transporter expression, can lead to toxic
      accumulation of compounds/xenobiotics cleared primarily by this route. During drug discovery
      and development, if in vitro evidence suggests renal transporters mediate excretion of a new
      chemical entity, the Food and Drug Administration recommends conducting a controlled clinical
      study to evaluate potential risks. These time-consuming and expensive clinical studies
      routinely involve adult participants and known substrates of renal transporters. However,
      such studies are not always feasible in children due to the enhanced potential for
      toxicities. This limitation led to the hypothesis that endogenous substrates could be used as
      surrogates, or biomarkers, of individual renal transporter function.

      Endogenous OCT substrates, such as 1-methyladenosine (m1A) and 1-methylnicotinamide (MNA), as
      well as OATs, such as homovanillic acid (HVA) and pyridoxic acid (PDA), are promising
      biomarkers of renal transporters in adults. However, using one or few such endogenous
      substrates can be misleading due to factors other than variability in specific renal
      transporter function. We propose to address this knowledge gap by using a panel of endogenous
      substrates/metabolites that recently has been identified as a robust biomarker of rodent Octs
      and Oats. Validation of these substrates/metabolites as biomarkers of OCTs and OATs in
      humans, both adults and children, will aid in the development of physiologically-based
      pharmacokinetic models that can be used to predict renal transporter-mediated xenobiotic
      excretion, drug-drug interactions, and toxicity in children.
    

Intervention name(s): MetFORMIN Oral Solution; Cimetidine 400 MG; Furosemide Oral Liquid Product; Probenecid 500 MG
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): liquid; tablet; oral solution; tablet
Other intervention name(s): Riomet; Tagamet; Lasix; Probalan
Intervention MeSH terms: Metformin; Probenecid; Furosemide; Cimetidine
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Kidney Transporter; Pharmacokinetics