Analysis Reveals that CPX-351 Shifts the Exposure of Cytarabine

Quantitative Whole Body Autoradiography (QWBA) Analysis Reveals that CPX-351 Shifts the Exposure of
Cytarabine (Cyt) and Daunorubicin (Daun) Away from Many Tissues While Providing Prolonged Exposure to
Cytotoxic Drug Concentrations in the Bone Marrow Compared to Conventional Free Drug Administration
Lawrence
1Celator
1
Mayer ,
Nicole
3
Sadowski ,
Paul
1
Tardi ,
Xiaowei
1
Xie ,
Donna
2
Cabral-Lilly ,
and Dennis
3
Heller
Pharmaceuticals Corp., Vancouver, BC, Canada; 2Celator Pharmaceuticals, Inc., Ewing, NJ, USA; 3Xenobiotic Laboratories, Inc., Plainsboro, NJ, USA
Introduction
CPX-351 Decreases The Extent and Rate of Tissue Drug Distribution
CPX-351 is a liposomal formulation co-encapsulating Cyt and Daun, that
delivers the drugs in vivo at a 5:1 molar ratio shown to be synergistic
preclinically. Clinically, CPX-351 has provided evidence of promising
improvements in patient outcomes, most notably in elderly newly
diagnosed high risk (secondary) AML and in unfavorable risk first
relapse adult AML where statistically significant increases in overall
survival where observed in two randomized, controlled Phase 2 studies.
In patients, CPX-351 displays a volume of distribution equal to the
plasma volume and first order elimination with a half-life of > 24h for
both drugs while maintaining the circulating Cyt:Daun molar ratio near
5:1. This is in contrast to the two drugs as conventionally administered
in non-liposomal (NL) aqueous solution form where very rapid drug
elimination is observed. Comparison of tissue distribution over time
between CPX-351 and NL Cyt:Daun was performed in rats to better
understand the pharmacodynamic relationships for CPX-351 in the
context of what is known for the non-liposomal (NL) drugs, particularly
as it relates to tissues relevant to efficacy and drug toxicity.
Cyt and Daun Levels in Toxicity Target Tissues
Cytarabine
Cytarabine
Treatment
[14C]Cytarabine
Tissue/Plasma
AUC Ratio
Daunorubicin
CPX-351
Hours after Administration
1
24
Gastrointestinal
tissues
NL
Esoph.
0.03 (Cyt)
0.09 (Daun)
1.90 (Cyt)
20.7 (Daun)
Intestine
0.04 (Cyt)
0.25 (Daun)
1.42 (Cyt)
64.8 (Daun)
Skeletal 0.01 (Cyt)
0.03 (Daun)
1.08 (Cyt)
17.8 (Daun)
Heart
0.12 (Cyt)
0.31 (Daun)
1.31 (Cyt)
29.3 (Daun)
Liver
0.11 (Cyt)
0.54 (Daun)
1.14 (Cyt)
27.4 (Daun)
Kidney
0.15 (Cyt)
0.39 (Daun)
2.81 (Cyt)
49.6 (Daun)
Non-Liposomal
Muscle
tissues
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 95-100 µCi/kg for Daun and 220 µCi/kg for
Cyt.
• Animals were sacrificed at the designated time points post-dose and
were frozen in a dry-ice/hexane bath in preparation for QWBA
procedures.
• Tissue distribution of test article-derived radioactivity was determined
using QWBA.
• Exposure of Cyt and Daun to a wide range of tissues was estimated
based on the tissue density of [14C]Cyt-derived or [14C]Daun-derived
radioactivity from QWBA section images.
• Tissue drug exposure comparisons between CPX-351 and NL
Cyt:Daun were performed using Cmax and AUC0-t values.
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 , X. Xie and D. Cabral-Lilly are are employees of Celator Pharmaceuticals, Inc.
CPX-351
Excretory
tissues
Daunorubicin
Treatment
[14C]Daunorubicin
Bone Marrow Cyt and Daun Exposure is Prolonged for CPX-351
Hours after Administration
1
48
Cytarabine
Daunorubicin
Non-Liposomal
*
*Cytarabine levels after 8hr were below the limit of quantitation
Conclusions
CPX-351
• CPX-351 limits early tissue distribution of Cyt and Daun compared to the drugs administered as the NL
formulation.
• With a few notable exceptions, tissues are exposed to lower drug levels for more prolonged periods of time after
CPX-351 vs. NL
• CPX-351 accumulates and persists in the bone marrow for over 4 days at concentrations known to have antileukemic activity against AML blasts.
• These results provide additional biologic rationale that support the clinical improvements in both efficacy and
safety seen for CPX-351 in randomized trials compared to conventional Cyt + Daun treatment.
Abstract No. 3740 Presented at the ASH 2014 Annual Meeting: December 6-9, 2014