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
Authors: Mayer Lawrence D , Sadowski Nicole , Tardi Paul , Xie Xiaowei , Cabral-Lilly Donna , Heller Dennis 
Published: October 2019

Background: 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.

Methods: Duplicate batches utilizing either [14C]Daun or [14C]Cyt CPX-351 or saline solutions of like labeled Cyt+Daun were prepared. Long-Evans 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 based on allometric scaling to reflect the respective clinical doses of CPX-351 and non-infusional Cyt:Daun treatment regimens. Animals were sacrificed at the designated time points post-dose and were frozen in a dry-ice/hexane bath in preparation for QWBA procedures. The 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.

Results: The rapid tissue distribution of Cyt and Daun following injection of the NL form of the combination was reflected by the recovery of <5% of either drug in the plasma 15 minutes after injection and tissue/plasma AUC0-t ratios that were >1 and >10 for [14C]Cyt and [14C]Daun, respectively, for the majority of tissues studied. In contrast, for CPX-351 virtually all of the injected Cyt and Daun was present in the plasma between 0.25-1.0 hours and corresponding tissue/plasma AUC0-t ratios in the majority of tissues were <0.05 and <0.2 for [14C]Cyt and [14C]Daun, respectively. These differences were readily apparent in the QWBA section images. For the NL form of the combination, [14C]Cyt and [14C]Daun were widely distributed throughout the body shortly after injection. Following CPX-351 administration, radioactivity was more limited to discreet tissues and organs. Distribution of Cyt into tissues after CPX-351 administration was reduced as well as much slower than after NL Cyt injection as reflected by markedly lower Cmax values in all non-vascular tissues as well as lower AUC values in a majority of tissues. Comparing [14C]Daun distribution for CPX-351 vs NL Daun revealed a slower removal from the blood/plasma compartment and gradual distribution to tissues for CPX-351 with a similar general tissue profile as for NL drug with the notable increases in exposure to spleen, liver, testis and bone marrow. Bone marrow levels of Cyt and Daun peaked at 24h post CPX-351 injection and persisted for several days at anti-leukemic concentrations; drug levels present in the marrow at 96h were well above the CPX-351 IC50 values previously observed with fresh AML patient blast samples. In contrast, bone marrow Cyt concentrations fell below detectable limits within 24h after administration of NL drug.

Conclusions: CPX-351 shifts the exposure of Cyt and Daun away from most non-hematologic tissues compared to NL drug treatment. Importantly, CPX-351 accumulates and persists in the bone marrow for over 4 days at concentrations known to have anti-leukemic activity against AML blasts. Taken together, 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.

Disclosures

Mayer: Celator: Employment, Equity Ownership, Patents & Royalties. Sadowski:Xenobiotic Laboratories: Employment. Tardi:Celator Pharmaceuticals: Employment, Equity Ownership. Xie:Celator Pharmaceuticals: Employment, Equity Ownership. Cabral-Lilly:Ceator Pharmaceuticals: Employment, Equity Ownership. Heller:Xenobiotic Laboratories: Employment, Research Funding.