Harmonization of Renal Function Assessment Is Needed During Early Clinical Development of Oncology Drugs.

Abstract

As with other therapeutic areas, the need to understand the disposition of antineoplastic drugs in patients who have hepatic and renal dysfunction is paramount during drug development to define the optimal dose in these special populations. Whereas renal impairment was originally thought only to alter drugs cleared by renal mechanisms, there is now both in vitro evidence that uremic toxins inhibit drug metabolism enzymes and transporters as well as clinical evidence that renal dysfunction can lead to alterations in the pharmacokinetics of drugs cleared primarily by hepatic mechanisms. Indeed, it is upon this basis that the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) recommended a dedicated renal impairment study for small-molecule drugs intended for chronic use regardless of their elimination pathways, that is, even for drugs that are eliminated by nonrenal pathways, in patients with varying degrees of renal impairment. For drugs eliminated mainly by nonrenal pathways, a reduced renal impairment study in patients with end-stage renal disease can be conducted (a reduced pharmacokinetic study). However, since 2010, even the reduced pharmacokinetic study design was not conducted for several FDA-approved oncology drugs (USPI and Summary Basis for Approval Documents), and the drug label information was instead based on results from population pharmacokinetic analyses. Traditionally, oncology diverges from general guidance documents during the conduct of early-phase clinical trials by making eligible patients with mild renal dysfunction. Oncology patients with a serum creatinine level within normal limits or with an estimated creatinine clearance (CrCl) level of greater than 60 mL/min are often eligible for early-phase clinical trials, which has led to a disconnect with the categorization of renal impairment by the FDA and the National Cancer Institute Organ Dysfunction Working Group. There is a need for harmonization of renal impairment categorization during the conduct of early-phase and renal impairment trials in oncology to ensure more precise dosing recommendations. In the article accompanying this editorial, Beumer et al sought to determine whether there is a safety concern for patients with cancer who are FDA-categorized as having mild renal impairment (CrCl, 60 to 90 mL/min) being eligible for early-phase clinical trials. The authors performed a retrospective assessment of 373 phase I studies sponsored by the Cancer Therapy Evaluation Program that were conducted over three decades (1979 to 2010) to determine whether patients in the FDA categorization of mild renal dysfunction experienced significant increases in toxicity, and if so, what potential long-term ramifications to oncology drug development may result. Beumer et al focused on singleagent phase I studies at the two highest dose levels to maximize sensitivity and to minimize confounding factors. The assessment was truncated to October 2010 to limit any confounding factors imparted by the isotope dilution mass spectrometry (IDMS)– traceable creatinine conversion in Clinical Laboratory Improvement Amendments laboratories. Beumer at alnoted that the estimated glomerular filtration rate (GFR) increased with time and attributed this increase to a trend of increasing patient weight during the threedecade assessment period. In trials using 179 drugs over broad therapeutic categories (eg, biologics, cytotoxic, and molecularly targeted agents), there was a small statistical difference between the mild renal dysfunction and normal renal function categories and the degree of grade 3 or 4 nonhematologic toxicity or any toxicity. Beumer at al concluded that the 3.7% change was not significant enough to warrant adjusting how early-phase clinical oncology trials are conducted and that the change supports the use of a modified study design to study only mild renal dysfunction if there is a difference in tolerability and pharmacokinetics in the moderate and severe renal dysfunction cohorts. We agree that conducting dedicated renal impairment trials is cumbersome during oncology drug development. As Beumer at al highlight, is it difficult to enroll patients in the severe impairment category onto trials because most patients at this extreme of renal impairment are on dialysis. An integrated assessment of the clinical pharmacology of a drug can often provide an understanding of the impact of renal impairment on pharmacokinetics and, ultimately, dose optimization. The assessment can include data from human mass balance, drug-drug interaction, hepatic impairment studies, and population pharmacokinetic analyses, and is similar to the approach takenwith the drug vismodegib, the results of which have been documented in its package insert. Although the article by Beumer at al focused primarily on those patients with renal function between the FDA categorization