Download Introduction CPX-351 Dramatically Increases Plasma Cyt and Daun

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
Lawrence Mayer1, Jeffrey Fulton2, Heasook Kim-Kang2, Yijun Yi2, Peter Wang2, Paul Tardi1, Xiaowei Xie1, and Dennis Heller2
1Celator
Pharmaceuticals, Vancouver, BC, Canada and Ewing, NJ, USA; 2Xenobiotic Laboratories, Inc., Plainsboro, NJ, USA
CPX-351 Dramatically Increases Plasma Cyt and Daun Concentrations
Introduction
Cyt and Daun Excretion Much Slower for CPX-351 vs Non-Liposomal Drugs
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 nonliposomal (NL) saline formulation has been associated with elevated and
prolonged exposure of the optimal drug ratio in bone marrow where drugloaded 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.
Cytarabine
Methods
• Duplicate batches utilizing either [14C]Daun or [14C]Cyt were prepared
for CPX-351 (5:1 molar ratio of Cyt:Daun) or saline solutions of like
labeled Cyt+Daun.
• Sprague-Dawley rats (4 per group) 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 noninfusional Cyt:Daun treatment regimens used in patients based on
allometric scaling.
• Radioactivity doses were 50 µCi/kg for Daun and 170-220 µCi/kg for
Cyt.
• Blood and plasma samples were collected and the concentrations of
total [14C] determined by liquid scintillation counting.
• Excreta, including bile, feces, and urine, were collected and quantified
for total [14C] by liquid scintillation counting.
• 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 from
HPLC analyses.
CPX-351 liposomes are bilamellar with a diameter
of 100nm for the outer vesicle. The membrane is
composed of DSPC: DSPG:Cholesterol in a 7:2:1
molar ratio. Cytarabine and daunorubicin, are
encapsulated in the aqueous space of both vesicles
at a 5:1 molar ratio. While inside the liposome,
daunorubicin is complexed with copper, as copper
gluconate, giving CPX-351 its characteristic purple
color. The strength of CPX-351 is 5 units/mL where
1 unit = 1.0 mg cytarabine plus 0.44mg daunorubicin
(base). The liposomes are suspended in 300 mM
sucrose.
Conflict of Interest Disclosure
L. Mayer, P. Tardi and X. Xie are are employees of Celator Pharmaceuticals, Inc.
Daunorubicin
CPX-351 Exhibits Extended Circulation Half-life and Much Greater Total Drug Exposure
Cytarabine
Daunorubicin
Cytarabine and Daunorubicin Metabolite Profiles are Similar
for CPX-351 and Non-Liposomal Drugs
Cytarabine and Daunorubicin Excretion Routes are Similar
for CPX-351 and Non-Liposomal Drugs
Conclusions
Cytarabine
•
•
•
•
Daunorubicin
Cytarabine is eliminated via urine
Daunorubicin is eliminated via bile/feces
Results for CPX-351 are from intact rats with samples collected over 2 weeks
Results for NL are from bile duct cannulated rats with samples collected over 72h
• 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 much slower drug excretion of Cyt and Daun for CPX-351 suggests that the burden on excretory and
metabolic systems may be reduced for CPX-351.
• Taken together, these results warrant additional clinical studies to examine whether CPX-351 provides an
improved safety profile for leukemia patients with hepatic or renal insufficiencies.
Abstract No. 2305, Presented at the ASH 2014 Annual Meeting: December 6-9, 2014