When to Conduct a Renal Impairment Study During Drug Development: US Food and Drug Administration Perspective

Abstract

To optimize drug therapy for individuals, it is critical to understand how various intrinsic (e.g., age, gender, race, genetics, organ impairment) and extrinsic factors (e.g., diet, smoking, concomitantly administered drugs) affect drug exposure and response.(1) Up to now, it has been far easier to discover effects on exposure caused by these factors, and the US Food and Drug Administration (FDA) has published several guidance documents with recommendations on how to evaluate these factors during drug development.

Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

“…Total RNA was extracted by the miRNeasy Mini Kit (Qiagen), and cDNA was synthesized using oligo (dT) [12][13][14][15][16][17][18] primer, deoxynucleotide triphosphate mix, RT buffer and MultiScribe™ Reverse Transcriptase (Applied Biosystems, Foster City, CA).…”

Update on the Pharmacokinetics and Redox Properties of Protein-Bound Uremic Toxins

“…However, even in the case of drugs that are primarily eliminated by metabolism or nonrenal transport, 25% have an approximately twofold increase in the area under the curve (AUC) in patients with severe kidney impairment, and thus require a significant dose reduction. 93,94 Namely, even drugs that are eliminated by nonrenal metabolism and transport could lead to important unintended consequences if they are administered without adjusting the dose to take into account reduced renal function. Previous animal studies suggest that, in kidney impairment, metabolic enzymes and transporters in the liver and intestine are downregulated or upregulated, thereby influencing the response to drugs that are subject to primarily nonrenal clearance.…”

Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

“…In the next stage, the validated WB-PBPK model was applied to predict bisoprolol pharmacokinetics in healthy adult subjects and patients with renal impairment after receiving multiple oral doses. GFR and creatinine clearance are accepted as the best overall measurement for assessing renal function [64] . The ratio of creatinine clearance in patients with renal impairment and normal adults was obtained from the original report [10] and then used to scale the renal clearance for the given population of renal-insufficient patients (age 59±5 years).…”

“…From these simulations, the means and variability of the pharmacokinetics of bisoprolol can be obtained before proceeding with clinical studies. Assuming that the exposure-response relationship is similar in subjects with normal renal function and subjects with impaired renal function [64] , the dose and dosing interval can be optimized and incorporated into a clinical trial design. Although more extensive validation is required in the future, the WB-PBPK model developed here is useful to gain the in vivo knowledge from in silico and in vitro studies to enable a priori adjustment of drug dosing for maximal efficacy and minimal toxicity.…”