Special Populations : Renal Impairment

Abstract

Kidney and liver are the main organs involved in the elimination of drugs. In general, the elimination capacity of the kidney is lower than of the liver, because of the smaller organ size and associated blood flow. Renal excretion can be limited by glomerular filtration rate in case of passive excretion or transporter capacity by total renal blood flow and in case of active secretion. Impaired renal function is a rather common condition in patients. Therefore, both dedicated studies in patients with renal impairment and pharmacokinetic investigations via means of population pharmacokinetics are routinely used in drug development to investgate if a dose adjustment needs to be applied in this vulnerable population. Purpose and Rationale Kidney and liver are the main organs involved in the elimination of drugs. Both have a metabolic and a direct excretory capacity, although the first is predominant for drugs eliminated by the liver, while the most frequent mechanism of renal clearance is direct excretion of the unchanged drug or its circulating metabolites. In general, the elimination capacity of the kidney is lower than of the G. Sanderink (*) Translational Medicine and Early Development, Sanofi-Aventis R&D, Vitry-sur-Seine, France e-mail: [email protected] A. Kovar Translational Medicine and Early Development, Sanofi, Frankfurt, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2019 F. J. Hock, M. R. Gralinski (eds.), Drug Discovery and Evaluation: Methods in Clinical Pharmacology, https://doi.org/10.1007/978-3-319-56637-5_8-1 1 liver, because of the smaller organ size and associated blood flow. Renal excretion can be limited by glomerular filtration rate in case of passive excretion or transporter capacity by total renal blood flow and in case of active secretion. Impaired renal function is a rather common condition, with an estimated 30 million people in the USA having chronic kidney damage (CDC 2018). Kidney function is well known to decrease with age and in our experience mild or moderate renal impairment is the norm in study populations above 75 years. It is therefore necessary to evaluate the potential impact of changes in renal function on drug pharmacokinetics in many cases, and not only for prescribing information including dose adjustment, but also in order to conduct a clinical development program in large patient populations with adequate exclusion criteria guaranteeing safe drug administration. The main rationale to evaluate the impact of renal impairment is when a drug or its active metabolites are mainly eliminated by renal excretion, especially when a drug is intended to be given in patients with decreased renal function (e.g., elderly patients) or augmented renal function (e.g., critically ill patients) and exhibits a narrow therapeutic margin. In such situations, dose adjustment may be warranted to reduce the risk of adverse drug reactions/toxicity and therapy failure, respectively. However, impaired renal function can also affect nonrenal drug elimination and has also been associated with other changes, such as changes in absorption, transport, and tissue distribution. Also plasma protein binding might play a role through decreased drug protein binding due to low albumin levels. This is of relevance for drugs with high plasma protein binding (>90%) and that have a high hepatic extraction ratio (>0.7). Another indirect mechanism of impaired renal function is uremic plasma that inhibits enzyme or transporter activity. For most drugs, the evaluation will focus on the effect of decreased glomerular filtration, but it should be kept in mind that renal (drug) transporters, expressed in the basolateral and apical membrane of renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney as well. Thus, in case of active renal secretion of a transporter substrate, there is also a potential for clinical significant drug-drug interactions with perpetrators that inhibit those transporters like cimetidine (OCT) or probenecid (OAT and OATP). Finally, the possibility that a drug is eliminated during hemodialysis needs also to be considered. As a consequence, for most drugs that are likely to be administered to patients with renal impairment – including drugs that are not primarily excreted by the kidney – the respective pharmacokinetics should be assessed in patients with renal impairment to provide appropriate dosing recommendations. Both guidance documents on renal impairment of the FDA and the EMA (US FDA Guidance for Industry 2010; EMA 2015) outline several approaches to study the effect of renal impairment on drug exposure. One approach is a population PK analysis of sparse data in large scale clinical trials, which allows to compare patients with reduced renal function with the typical patient for a given indication. Some limitations of this approach are that it does not address patients that are voluntary excluded from such studies, which is generally the case for severe and end-stage renal impairment. Also some specific parameters like unbound drug fraction and circulating metabolites may need to be included in the evaluation, and the sample size should provide sufficient sensitivity. However, the approach may be very useful to confirm the absence of a treatment risk for patients with renal disease, especially when it is not easily feasible to conduct a specific study in renally impaired subjects without the clinical indication. When a specific pharmacokinetic study in subjects with decreased renal function is conducted, it can be done according to a “full” design or according to a “reduced” or “staged” design. In the first case, all degrees of renal impairment are included in the study. In the reduced design, the effect of severely decreased renal function in comparison to normal renal function is investigated first. If the results indicate that also other degrees of renal impairment may alter the pharmacokinetics of the study drug to a clinically relevant extent, 2 G. Sanderink and A. Kovar