Pharmacokinetic (PK) data guide the safe and effective management of a drug treatment; however, with diabetic patients, PK studies can be especially challenging. Varying degrees of kidney disease in patients can affect the PK characteristics of the drug and the reliability of the study results.
From screening patients to determining doses, testing a drug for diabetic patients involves several important considerations.
The importance of early work
Even before a drug reaches the clinical stages, early work can help set the stage. Preclinical research is very important in identifying agents with activity in the diabetic spectrum, while studies in early toxicology provide valuable direction as to whether the risks are acceptable in the diabetic population.
Given that most diabetic drugs affect the kidneys, performing an early renal study on a model can determine if the drug has a future in the diabetic space and may help guide earlier go/no-go decisions ‒ before allocating additional resources to the efforts.
Understanding the severity of diabetic kidney disease
Once in the clinic, researchers need to determine the appropriate dose for patients with diabetic kidney disease. When kidney function is impaired and a drug is excreted through the kidneys, a modified dose may be required. For a population with severe renal impairment, researchers might choose to exclude these patients from the studies.
The FDA draft guidance, Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling, can be a helpful starting point to understand the complex issues associated with these PK studies.
Forming a study design strategy
One study design strategy involves starting with approximately eight patients in the mild category for renal impairment, which is defined as a mild decrease in estimated glomerular filtration rate (eGFR).
Based on the data gathered from this cohort, researchers may make the determination to proceed to the next stage of kidney impairment, a moderate decrease in eGFR. These data can also be matched to healthy individuals that correlate closely to the BMI, age, gender and ethnicity of the study groups, comparisons that help illuminate information about the drug’s clearance and possible side effects in select populations.
Modifying the guidance
In some cases, it’s necessary to modify the FDA guidance to accommodate for certain PK studies. Any specific modifications to the guidance are not intended to weaken the study or avoid tests. Rather, these changes strengthen the guidance to better align it with the tested drug and patients.
Our researchers typically start by screening potential patients, relying on established relationships with sites experienced in handling renal impairments. The screening looks at an entire safety profile by evaluating current medications, measuring blood glucose levels and performing cardiograms in addition to general physicals. If a candidate passes the first screening, a second screening assesses their level of renal impairment.
Dealing with shifts in renal impairment
While the level of detail gathered in the initial screening delivers valuable information, it’s important to note that patients tend to have fluctuations in measured renal impairment, which can be affected by diet, physical activity and even levels of hydration. Researchers must determine if a patient is stable and healthy enough to participate in a study by gathering a full history of values beyond a cursory check.
For example, if a patient has moderate levels of impairment near the bottom of the moderate range or sometimes tests in the severe range, researchers should not classify the patient in moderate category. Researchers often direct the sites to rescreen or validate a patient if they are in-between ranges. This ensures no candidate is more than 20% out of their initial range, allowing for more robust data and reliable results.
During the studies, patients can be dosed in units that are capable of drawing many PK values to characterize the curves or levels of the drug. Again, maintaining stability of renal impairment is important to standardize the testing approach.
Ultimately, PK data should represent what prescribing physicians would expect in the real world. If there is an observed change in the PK parameters, these data will help advise the physicians on the label and determine if their patients will benefit from the treatment.
This article is part of a six-part series on Diabetic Kidney Disease. Each Thursday we’ll publish a new entry. Check back next week for part two.