CPX-351 Markedly Reduces Renal and Hepatic Clearance Rates for Cytarabine (Cyt) and Daunorubicin (Daun) in Rats with an Associated Decrease in Excretory and Metabolic Burden Despite Providing Dramatic Increases in Systemic Drug Exposure Compared to Conventional Cyt+Daun
Authors: Mayer Lawrence D , Fulton Jeffrey , Kim-Kang Heasook , Yi Yijun , Wang Peter , Tardi Paul , Xi Xiaowei , Heller Dennis 
Published: October 2019

Background: CPX-351 is a liposome formulation of Cyt and Daun in which the 5:1 molar ratio of the two drugs optimizes synergy. The marked increase in efficacy observed preclinically for CPX-351 versus the combination given in a non-liposomal (NL) saline formulation has been associated with elevated and prolonged exposure of the optimal drug ratio in bone marrow where drug-loaded liposomes are preferentially taken up by leukemia cells. Clinically, CPX-351 has provided evidence of promising improvements in patient outcomes, where statistically significant increases in overall survival were observed in unfavorable/poor risk AML patient populations in two randomized Phase 2 studies. While prolonged exposure to very high drug concentrations in plasma and systemic maintenance of the 5:1 molar Cyt:Daun ratio provided by CPX-351 has scaled allometrically from rodents through to humans, little was known about its excretion and metabolic properties. Comparison of drug excretion and metabolism over time between CPX-351 and the combination NL formulation was performed in rats to better understand the pharmacodynamic relationships for CPX-351, particularly as it relates to implications for patients exhibiting reduced renal or hepatic capacity.

Methods: Duplicate batches utilizing either [14C]Daun or [14C]Cyt CPX-351 or saline solutions of like labeled Cyt+Daun were prepared. Sprague-Dawley rats received single IV bolus doses of either 15 units/kg (15 mg/kg Cyt + 6.64 mg/kg Daun) CPX-351, or a saline solution of 300 mg/kg Cyt + 10 mg/kg Daun. These doses were selected to reflect the respective clinical doses of CPX-351 and non-infusional Cyt:Daun treatment regimens used in patients based on allometric scaling. Excreta, including bile, feces, and urine, were collected and quantified for total [14C]. Blood and plasma samples were collected and the concentrations of total [14C] determined. Pharmacokinetic parameters of the administered drug were estimated based on total [14C] content. The profiles of parent drugs and their metabolites were determined in plasma, bile, urine and fecal samples using [14C]-radioprofiles.

Results: Cyt and Daun exhibited slower plasma clearance when administered as CPX-351 compared to the NL formulation in saline. For CPX-351, virtually all of the injected dose was present unchanged in the plasma 1h post injection and ~25% remained at 24h, whereas only 4% and 1% of the administered Cyt and Daun, respectively, were present in rats given NL drug 0.25h after injection. Total cumulative [14C]Cyt excretion was >95% of the injected dose for both formulations. Although elimination of CPX-351 is expected to be mediated by RES tissues in liver and spleen, >95% the administered [14C]Cyt was recovered in the urine for this group, similar to results observed with NL Cyt. [14C]Cyt recovery in total excretia post injection reached 80% of the injected dose within 8h and 48h for NL and CPX-351, respectively. For [14C]Daun in CPX-351, roughly 75% of the administered dose was excreted via the feces, similar to NL Daun. [14C]Daun total excretia recovery in bile, feces and urine after administration of the NL formulation reached 60% of the administered dose within 24h and 77% within 48h. Excretion of CPX-351 [14C]Daun was significantly delayed where only 14% and 52% of the administered dose was recovered in bile, feces and urine within 24h and 96h, respectively. Metabolic profiling revealed that parent drugs predominated in bile and urine for both drugs, regardless of the formulation. Additional metabolism of Daun occurred in the gut with the appearance of new metabolites, however, no significant differences were observed between CPX-351 and NL.

Conclusions: The profile of Cyt and Daun excretion/metabolism following CPX-351 administration is qualitatively similar to that for the NL drug combination. The primary difference in drug elimination between these two treatments is the markedly slower rate of hepatic and urinary clearance for both drugs given as CPX-351. The fact that total Cyt and Daun doses administered to patients as CPX-351 are lower than those in NL regimens plus their slower drug elimination, suggests that the burden on excretory and metabolic systems are reduced for CPX-351. These results warrant additional clinical studies to examine whether CPX-351 provides an improved safety profile for leukemia patients experiencing hepatic or renal insufficiencies.

Disclosures

Mayer: Celator: Employment, Equity Ownership, Patents & Royalties. Fulton:Xenobiotic Labs: Employment, Research Funding. Kim-Kang:Xenobiotic Labs: Employment, Research Funding. Yi:Xenobiotic Labs: Employment, Research Funding. Wang:Xenobiotic Labs: Employment, Research Funding. Tardi:Celator: Employment, Equity Ownership. Xi:Celator: Employment, Equity Ownership. Heller:Xenobiotic Labs: Employment, Research Funding.