The FDA require that certain investigational drugs be evaluated to determine if impaired renal (kidney) function alters a drug’s pharmacokinetic profile and if such change necessitates modification of the dosing regimen/dosing guidelines relative to patients with normal renal function. In general, this requirement applies mostly to drugs that are primarily excreted by the kidney (i.e., if the fraction of dose excreted unchanged in the urine is at least 30% for either the parent drug or significant active metabolite). Also, assessment of pharmacokinetics in subjects with renal impairment typically is needed in an NDA submission for chronically administered drugs (both small molecules and possibly biologics), for drugs indicated in patients on dialysis, and for 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, should a drug be evaluated via a standalone renal impairment study or within the context of late phase studies (i.e., using a population PK/sparse sampling approach in a patient population enriched with varying degrees of renal impairment)? There are also a number of drugs for which a standalone renal impairment study is not necessary or required.
Overall, the main objective of clinical pharmacology renal impairment investigations are to determine if the pharmacokinetics of a drug and/or its active metabolites are mechanistically altered at different stages of renal impairment/dysfunction, which would influence dosing recommendations / dose adjustments for patients. As the study’s success depends on pharmacokinetics, proper study set-up, study execution, and PK analysis is critical and Nuventra’s pharmacokineticists and clinical pharmacology consultants have the experience to ensure success.
Scientific & PK Considerations
1) 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 in a development program 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 for the drug to be studied and not just healthy young males. 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.
Also, dose strength must be considered in this study since 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 also advise on frequency of sample collection (plasma and urine) to enable a robust assessment of pharmacokinetics.
2) 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 5 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.
3) 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 nonrenal clearance, apparent volume of distribution (V/F), 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)
When to Execute Renal Studies in Development Programs?
The timing around 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 de-risk the continued development of a drug.
Read more in the FDA Guidance “Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling.”