The kidneys, which are part of the urinary (or renal) system, play a critical role in filtering drugs and other compounds from the blood. Renal impairment occurs when the kidneys are not functioning properly. Renal impairment can range in severity from mild impairment to end stage renal disease (i.e., kidney failure).
The FDA requires that certain investigational drugs be evaluated to determine if impaired renal (kidney) function alters a drug’s pharmacokinetic (PK) profile. If so, then this may necessitate modifying the dosing regimen and dosing guidelines compared to patients with normal kidney function. In general, this requirement applies to drugs that are primarily excreted by the kidney, meaning that the amount of unchanged dose excreted in the urine is at least 30% for either the parent drug or significant active metabolite.
PK assessment in subjects with renal impairment is typically required for NDA submission for the following types of drugs: chronically administered (both small molecules and possibly biologics), drugs indicated in patients on dialysis, and drugs that are expected to be administered to patients with varying degrees of renal impairment post-approval.
There are many exceptions and nuances to consider when determining the proper strategy for evaluating how renal impairment PK data should be collected. For example, renal impairment can be evaluated by a standalone renal impairment study or within the context of late phase studies by using population PK/sparse sampling approaches in patient populations enriched with varying degrees of renal impairment. There are a number of drugs for which a standalone renal impairment study is not necessary or required. Learn how to potentially avoid a renal impairment study altogether with proper study design and population PK modeling approaches.
Overall, the main objective of clinical pharmacology renal impairment investigations are to determine if the PK of a drug and/or its active metabolites are altered at different stages of renal impairment/dysfunction. This influences dosing recommendations and dose adjustments for patients. PK analysis is critical because a study’s success depends on pharmacokinetics, proper study set-up and study execution.
Scientific & PK Considerations
Reduced PK Study Design
The FDA’s guidance to the industry suggests a bootstrap method for assessing any effect on PK from impaired renal function. The FDA recommends that a “reduced PK study” be conducted first to compare the PK parameters in End Stage Renal Disease (ESRD) patients not yet on dialysis with the PK in “matched” subjects with normal renal function.
If differences in certain PK parameters are noted between the two groups then the FDA recommends a full PK study design (see below). The “matched” controls are subjects from the typical patient population with “normal” renal function. The reduced study design can be conducted either as a single dose or multiple dose study depending on the expected pharmacokinetic behavior of the drug.
Dose strength must be considered in a reduced study design because impaired renal function might lead to higher exposures and safety concerns for the study population. An experienced pharmacokineticist can quickly and efficiently determine if any dose adjustments are needed in a renal impairment study and advise on frequency of sample collection (plasma and urine) to enable a robust assessment of pharmacokinetics.
Full PK Study Design
If a full PK study is needed based on data generated from the reduced PK study then, per the FDA’s guidance on renal impairment studies, the study will investigate the pharmacokinetics of the investigational drug in five types of subjects with varying degrees of renal impairment (Stages 1 through 5).
- Stage 1: Control (normal glomerular filtration rate; GFR)
- Stage 2: Mild decrease in GFR
- Stage 3: Moderate decrease in GFR
- Stage 4: Severe decrease in GFR
- Stage 5: End Stage Renal Disease (ESRD)
Subjects throughout the 5 stages of renal impairment should be matched for age, gender, race, weight and other factors. Sample size will depend on the expected variability in pharmacokinetics within subjects across the different stages.
Population PK Analyses
Population PK analyses can be conducted with sparse sampling of drug concentrations from patients enrolled in late stage studies. The studies need to be enriched for patients with varying degrees of renal impairment to enable population PK analyses and modeling the relationship between renal function and PK parameters such as: AUC, Cmax, apparent clearance (CL/F), apparent non-renal clearance, apparent volume of distribution (V/F), and terminal half-life (t1/2).
Nuventra has successfully guided clients into population PK analyses within already planned Phase 3 studies; thereby avoiding the expense of conducting standalone renal impairment clinical pharmacology studies (i.e., avoiding the reduced and full PK studies). Learn more about when avoiding a standalone renal impairment study may be possible.
The timing around the execution of impaired renal function studies depends on multiple factors including interactions with regulatory authorities, funding, investor expectations, exit strategies, and overall clinical development plans to support future studies or to de-risk the continued development of a drug.
Nuventra’s pharmacokineticists and clinical pharmacology consultants have the experience to ensure success regarding renal impairment studies. Contact us to find out if a full or reduced renal impairment study is required for your program.