CERSI Collaborators: Kathy Giacomini, PhD (UCSF), Tim Meyer, MD, Stanford University
FDA Collaborators: Ruth Barratt, PhD, DVM, Lei Zhang, PhD, Shiew-Mei Huang, PhD,
Issam Zineh, PharmD, MPH, Ming-Liang Tan, PhD
Project Start Date: April 2014
Regulatory Science Challenge
The kidney (renal system) plays a protective role in the body by removing drugs, waste, and toxic substances. Kidney disease affects the ability of the kidneys to eliminate drugs from the body. Therefore, in individuals with kidney disease the administration and dosage of certain drugs need to be reduced so that their kidneys can effectively eliminate the drugs. Methods to predict whether new drugs will have toxic effects in patients with renal impairment and to predict the dosages of the new drugs will help inform treatment decisions and avoid unwanted side effects.
Project Description & Goals
High levels of serum creatinine, a key marker to monitor kidney function, are interpreted as a decrease in renal health. In some cases, new drugs increase serum creatinine levels by inhibiting specific transporters in the kidneys. This may be incorrectly interpreted by clinicians as renal toxicity. These “false positives” could lead to discontinuing the use or development of a promising new drug.
Researchers will study the mechanisms involved in serum creatinine changes, identifying what transporters are involved in creatinine clearance and developing models to predict how changes in kidney function affect creatinine clearance. In addition, researchers will continue to evaluate how other toxic molecules that result from kidney disease affect various metabolic and transport processes This project’s goals are to:
1. broaden understanding of the renal transporters involved in drug clearance and use serum creatinine levels or alternate markers to define the potential toxicity of a new drug and
2. improve the ability to predict potential systemic (and local tissue) exposure changes of drugs in the presence of kidney disease.
Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3. Hsueh CH, Yoshida K, Zhao P, Meyer TW, Zhang L, Huang SM, Giacomini KM. Mol Pharm. 2016 Aug 9. [Epub ahead of print], PMID: 27467266.