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  5. Guidance Recap Podcast | Pharmacokinetics Study Design Considerations in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing
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Guidance Recap Podcast | Pharmacokinetics Study Design Considerations in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing

Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Martina Sahre, a Policy Lead on the Guidance and Policy Team in CDER’s Office of Clinical Pharmacology. She will be sharing some thoughts with us on the newly published final guidance titled, “Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing.” Welcome, Dr. Sahre! Thank you for speaking with us today.


For listeners less familiar with this topic, could you provide some background about the kidney’s role in drug excretion and explain how impaired renal function can affect drug dosing?

Yes, well the kidneys play an important role in the process of drug excretion. They filter the blood, get rid of waste products, including drugs and their metabolites, and remove the waste products from the body into urine.

Drug excretion from the kidneys is a complex interplay between three processes:

  • First, there is glomerular filtration, where blood is filtered through the glomerulus, marking the initial removal of substances from the bloodstream.

  • Second, there is tubular secretion, a process where drugs or their metabolites are transported into the renal tubules from the blood, playing a critical role in compound excretion.

  • Third, there is tubular reabsorption, where certain substances are selectively reabsorbed back into the bloodstream from the renal tubules, which is essential for the body's balance of these substances.

When the kidneys are not functioning well, it can significantly impact the clearance of drugs that are eliminated via the renal route. For example, impaired renal function could lower the rate of glomerular filtration, which can then influence drug elimination. In patients with chronic kidney disease, this can lead to an increase in the concentration of the drug in the blood, potentially leading to toxic effects.

Hence, it is important to characterize, the impact of impaired renal function on drug PK to derive appropriate dosage recommendations for patients with renal impairment.

Under what circumstances should stand-alone studies to evaluate the impact of renal impairment on PK be considered?

Generally, there are three main considerations for when a standalone study should be conducted:

  • First, when over 30% of bioavailable drug or its active ingredients are excreted through urine, a standalone renal PK study across a broad spectrum of renal function, from normal to severely impaired, should be conducted.

  • Second, for drugs with less than 30% renal excretion, an abbreviated approach may be sufficient. Initially, the focus is to characterize PK in individuals with severe renal impairment. Such a study is also referred to as reduced design study. If significant alterations in drug levels are found, the study can be expanded to include individuals with less severe impairment in kidney function.

  • Lastly, a standalone study should be considered for evaluation of the impact of dialysis or renal replacement therapy on PK, where appropriate.

We hear that often patients with renal impairment are excluded in late-phase trials, how can drug developers enable inclusion of patients with impaired renal function in late-phase trials?

There are multiple ways drug developers can potentially work to include patients with impaired renal function in late-phase trials.

For example, drug development programs have the capability to embark on dedicated PK studies early in the development process. Early assessment can help inform the enrollment strategy for patients with renal impairment in clinical trials. Further, the assessment of all available data using model and simulation tools can help determine whether further assessment is needed or if dose adjustments can be made to accommodate a broader inclusion of participants with impaired renal function. Additionally, drug developers have the opportunity to implement innovative study designs such as adaptive enrollment or sequential evaluation, and so forth to facilitate the inclusion of patients with various levels of renal function in Phase 2 and 3 trials.

In general, we encourage drug developers to take a proactive approach to ensure that dosage recommendations for safe and effective use are available for patients across the spectrum of renal function at the time of initial approval.

In the guidance you also talk about renal replacement therapy. Could you explain why that is an important aspect to consider?

In patients with end stage kidney disease, or in acute kidney injury, the kidney function is diminished to such an extent that intrinsic kidney function is supplemented by renal replacement therapy.

The different types of renal replacement therapy that we are referring to here include intermittent hemodialysis and continuous renal replacement therapy (also called CRRT). These modalities can potentially remove the drug from the body, thereby potentially impacting the drug’s efficacy. Therefore, in the guidance, we recommend standalone studies to be conducted for the relevant modalities to determine if dosage adjustments are needed. Since CRRT methodologies are different from intermittent modalities, the recommendations for patients receiving CRRT can differ from this on intermittent therapy.

Can the effect of impaired renal function on drug exposure be characterized in Phase 2 and 3 trials?

Yes, the effect of renal impairment on drug exposure can potentially be characterized in Phase 2 and 3 trials. If adequate PK sampling is conducted in these trials, the collected data may provide enough information to understand the influence of renal function on drug exposure. However, if data from these trials is insufficient, for example if patients with severe renal impairment were not enrolled, the sponsor may need to conduct a standalone study to evaluate the PK in the missing renal function range.

In the guidance, I saw that there was discussion of the assessment of renal function. Dr. Sahre, could you highlight the importance of assessing renal function in the context of the characterization of renal impairment on PK or PD of a drug?

Kidney function is usually assessed using the Glomerular Filtration Rate (also called GFR), which is considered a good marker of renal function.

In general, there are three ways to assess renal function for the purpose of conducting a renal impairment study:

  • The first approach is to measure glomerular filtration rate using an intravenously injected exogenous marker. In this case, the disappearance rate of the exogenous marker is assessed. This is called measured GFR. An example of such an exogenous marker is inulin, generally considered a gold standard, but the measurement of GFR is generally reserved for specialized centers due to the complexity and time it takes to measure.

  • The second approach relies on serial measurements of an endogenous marker, such as creatinine in urine over 24 hours. This measure is called measured creatinine clearance.

  • The third and most commonly used approach, is to estimate GFR based on a single point measurement of an endogenous marker in serum, here that would be either creatinine or cystatin C. The medical community has developed equations that incorporate the measurements of the endogenous markers together with demographic factors to provide an estimate of GFR.

While the guidance supports use of any modern method to ascertain renal function in PK studies, we recommend using estimated GFR, also known as eGFR due to their widespread acceptance and frequent reporting by laboratories.

The guidance recommends using the reported value of estimated GFR in mL/min/1.73 m2 re-calculated for the patient’s actual body surface area. Can you talk about the rationale behind that recommendation?

The GFR estimating equations were developed based on measured GFR indexed to an average body surface area of 1.73 m2. This allows comparison of GFRs in the population to define what constitutes impaired renal function for the purpose of diagnosing, staging, and treating kidney disease. Many estimating equations for GFR report the value in units of mL/min/1.73 m2.

However, when it comes to dosing drugs in a patient with renal impairment, it is that patient’s own renal function, that determines the capacity to clear any given drug. Hence, the patient’s body surface area should be utilized to estimate the GFR and not indexed to a body surface area of 1.73 m2.

To address this concern, the guidance recommends dividing the reported eGFR value by 1.73 and multiplying by the patient’s own body surface area. The resulting eGFR will have units of mL/min, which are the relevant units of renal function for the purpose of drug dosing.

What other factors should be considered when deriving dosage recommendations for drugs in relation to renal impairment?

The guidance provides suggestions for considering the relationship between renal function, drug exposure, and the exposure response relationship for both safety and efficacy to derive dosage recommendations. In addition, it recommends using a reference group with an acceptable risk-benefit profile, meaning it does not have to be the normal renal function group per default.

For our final question, what are a couple of key items from the guidance that you especially want your listeners to remember?

Well, first that it is important to consider the impact of renal impairment on the PK of a drug early in drug development. This helps to facilitate the inclusion of patients with renal impairment in late phase clinical trials. If patients with renal impairment are excluded, that exclusion should also be justified.

And then further, the assessment of kidney function is based on either measuring or estimating it. When it comes to assessment of kidney function for the most part estimation of GFR is a reasonable approach for a standalone renal impairment study. In general, we recommend using eGFR due to widespread acceptance and frequent reporting by laboratories. Then lastly, when eGFR is estimated it is often reported in units of mL/min/1.73 m2 (i.e., standardized to a body surface area of 1.73 m2). For the purpose of dosage adjustment, the units should be mL/min, as it reflects the individual’s renal function.

Dr. Sahre, thank you for taking the time to share your thoughts on the final guidance on pharmacokinetics study design considerations in patients with impaired renal function. We have learned so much from your insights on this document. We would also like to thank the guidance working group for writing and publishing this final guidance.

To the listeners, we hope you found this podcast useful. We encourage you to look at the snapshot and to read the guidance.

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