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  1. Advancing Regulatory Science

Renal Impairment in New Drug Development

CERSI Collaborators: Stanford University: Timothy Meyer, MD; Tammy Sirich, MD
University of California San Francisco (UCSF): Kathy Giacomini, PhD (UCSF)

FDA Collaborators: Center for Drug Evaluation and Research (CDER): Shiew Mei Huang, PhD; Lei Zhang, PhD; Qi Liu, PhD; Ruth Barratt, PhD, DVM; Issam Zineh, PharmD, MPH; Ming-Liang Tan, PhD

Project Start Date: April 2014
Project End Date: July 2024

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 and 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.

In Phase I of this project, which concluded in September 2016, researchers studied 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 continued to evaluate how other toxic molecules that result from kidney disease affect various metabolic and transport processes. This project’s goals were 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.

Phase II of this project, which began in October 2020, assessed the effect of metolazone, a diuretic, on the clearance of waste solutes that are normally secreted by the kidneys when compared to a placebo drug. The effect on urine volume will also be assessed. Diuretics are commonly used to increase urine output in patients on hemodialysis who still produce some urine to limit fluid accumulation. Diuretics and endogenous waste solutes are cleared by the same kidney transport systems. Patients on hemodialysis who still produce urine were administered metolazone and placebo in a cross-over study design. This project assessed the effect of metolazone versus placebo on the clearance of waste solutes that are normally secreted by the kidneys. The effect on urine volume was also assessed.

Research Outcomes/Results

The COVID-19 pandemic disrupted human subject research at study sites, greatly hindered study enrollment, and ultimately did not permit researchers to draw conclusions on the effect of metolazone on the clearance of secreted waste solutes. UCSF-Stanford CERSI optimized methods to measure metolazone and secreted solutes. Investigators hypothesize that the administration of drugs cleared by the kidney impairs the clearance of the body’s waste products, and thereby has the potential to increase their plasma levels worsening symptoms of reduced kidney function.

Publications

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

 

 

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