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U.S. National Institutes of Health
Last Updated: 05/20/15

Organ Dysfunction Studies

Recognizing that there is a significant need to conduct studies in patients who have organ dysfunction, the Investigational Drug Branch performs studies of investigational agents just prior to potential licensing for therapeutic indications by the FDA. The primary goals and objectives of these study initiatives are outlined below:

  • To determine when studies of PK in patients with organ dysfunction should be performed and when they may be unnecessary;
  • To design and conduct of PK studies in patients with organ dysfunction;
  • To define inclusion criteria for patient populations to be studied;
  • To design and conduct PK studies in patients with hepatic and renal dysfunction including those post hepatic and renal transplant or with end-stage renal disease (ESRD) patients treated with dialysis (hemodialysis or peritoneal dialysis);
  • To analyze and report the results of these studies in peer-reviewed journals;
  • Representation of organ dysfunction study results in approved product labeling that provides guidance for dosing based on degree of hepatic or renal dysfunction.

The kidneys, as excretory, biosynthetic and metabolic organs, have a vital role in normal physiology. In the United States, approximately one in nine adults has chronic kidney disease (CKD) and a minority suffer from its terminal complication, end stage renal disease (ESRD). CKD is usually silent until its late stages, and without aggressive screening, detection may not occur until immediately before symptomatic kidney failure develops. A diagnosis of renal impairment has serious repercussions for many drugs excreted by the kidneys. Most obviously, renal impairment may decrease excretion of drugs or their metabolites, leading to accumulation and potential toxicity. But additionally, renal impairment has the potential to affect drug absorption, hepatic metabolism, plasma protein binding, and drug distribution. As renal impairment progresses from mild to moderate or severe, these changes become more pronounced.

Hepatic dysfunction is much more common than renal dysfunction in the oncology patient population, and its main functions—metabolizing drugs or promoting the excretion of unchanged drugs or metabolites in the bile—is crucial for may drugs. In the United States, drug-induced liver injury (DILI) is now the leading cause of acute liver failure (ALF), exceeding all other causes combined. Acknowledging that drugs have the potential to injure patients’ livers seriously—contributing to illness, disability, hospitalization, life-threatening liver failure, the need for liver transplantation and sometime causing death—the FDA and several other organizations are increasing efforts in this area.