Assessment of the Impact of Renal Impairment on Systemic Exposure of New Molecular Entities: Evaluation of Recent New Drug Applications

The US Food and Drug Administration (FDA) is currently developing a guidance for industry to replace a previous guidance, "Pharmacokinetics in Patients With Impaired Renal Function--Study Design, Data Analysis, and Impact on Dosing and Labeling" (renal guidance) issued in May 1998. The impact of the 1998 renal guidance was assessed following a survey of 94 new drug applications (NDAs) for small-molecule new molecular entities (NMEs) approved over the past 5 years (2003-2007). The survey results indicate that 57% of these NDAs included renal impairment study data, that 44% of those with renal data included evaluation in patients on hemodialysis, and that 41% of those with renal data resulted in recommendation of dose adjustment in renal impairment. In addition, the survey results provided evidence that renal impairment can affect the pharmacokinetics of drugs that are predominantly eliminated by nonrenal processes such as metabolism and/or active transport. The latter finding supports our updated recommendation to evaluate pharmacokinetic/pharmacodynamic alterations in renal impairment for those drugs that are mainly eliminated by nonrenal processes, in addition to those that are mainly excreted unchanged by the kidney.