Around a third of prescribed drugs are primarily renally eliminated from the body. Unsurprisingly, the influence of renal impairment on drug disposition and ultimately clinical dose is routinely investigated during drug development.
The FDA recently issued Draft 2 of its Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing. The document provides comprehensive guidance on when and how to investigate impaired renal function for an investigational drug. In addition, to the labelling claims that can be made in respect of study outcome.
In the guidance one of the criteria for doing a study is if the drug or its active metabolites are substantially eliminated by the renal route. Substantial elimination is helpfully defined as occurring when the fraction eliminated unchanged in the urine is ≥0.3. Interestingly, biologics are detailed for the first time. Peptides with a molecular weight less than 69kDa can be renally cleared and the influence of renal impairment for such products is recommended.
The FDA note that there are several ways to assess renal function. Exogenous markers such as inulin and EDTA have been used to determine glomerular filtration rate (GFR). It is acknowledged that these methods are not routinely used in clinical practice and that equation based estimations using serum creatinine are sufficiently robust for pharmacokinetic studies. This is in contrast to the EMA guidance on renal impairment where their preference is for the more accurate exogenous methods to be used to define GFR. Nevertheless, the EMA will accept equation based estimations if the bioassay for creatinine has been suitably referenced.
Overall, potentially a useful update for this important area of drug development.