Cytotoxic Anticancer Agents and Renal Impairment Study: The Challenge Remains

Although clinical trials for drug approval are conducted in patients with normal renal function, cancer patients in clinical practice may have compromised renal function because of the underlying disease or for other causes such as aging, diabetes, infectious and autoimmune diseases, or drug-related toxicities. 2] This practice is suboptimal, and definitely does not benefit the organ dysfunction patients who may have no available therapy at the launch of the drug. The US Food and Drug Administration reviews the results of the studies, and any other necessary information subsequently submitted for inclusion in the drug label. Absence of information in the drug label poses a significant challenge to the treating physicians on how to select appropriate drug doses for patients. In the era of oral and targeted therapy and in the adjuvant and prevention setting, when patients may be on daily continuous therapy, drug accumulation because of organ dysfunction can be severe and result in acute and long-term undesirable effects. ] The study was a phase I, dose escalation, safety, and pharmacokinetic study to determine adequate pemetrexed starting dose in patients with compromised renal function. The study had four cohorts based on glomerular filtration rate (GFR) as a measure of renal function in the patients. GFR was measured by serum technetium-99m diethylenetriamine penta-acetic acid ( 99m Tc-DTPA) clearance. The GFR groupings were one through four with a GFR of 60 mL/ min, 40 to 59 mL/min, 20 to 39 mL/min, and less than 20 mL/min, respectively; group 1 was subdivided, A and B, with GFRs 80 mL/min and 60 to 79 mL/min, respectively, and group 3 was subdivided, A and B, with GFRs of 30 to 39 mL/min and 20 to 29 mL/min, respectively. The patients were treated with a 10-minute infusion of 150 to 600 mg/m 2 pemetrexed dose once every 3 weeks. Dose escalations were performed within each GFR group and were independent from the other GFR groups.