Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals

• Published in: Nanomedicine Vol. 30; p. 102275
• Main Authors: Wang, Qi, Tardi, Paul, Sadowski, Nicole, Xie, Sherwin, Heller, Dennis, Mayer, Lawrence
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2020
• Subjects: Acute myeloid leukemia; CPX-351; Drug metabolism; Pharmacokinetics; Tissue distribution; BDC; LLOQ; QWBA; LC–MS/MS; AUC; MPS; SD; AUCtot; t1/2; CMC; Drug metabolism; LSC; HPLC; AML; Cmax; UV; CL; T:P; Ara-U; NC; ND; LC; Tmax; Vss; Tissue distribution; Pharmacokinetics; Acute myeloid leukemia; CPX-351
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2020.102275

CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally <1 versus >1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies. CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio. Preclinical studies showed slow and similar release of cytarabine and daunorubicin following CPX-351 administration. In addition, dramatically different tissue distribution and lower unbound plasma and tissue concentrations of cytarabine and daunorubicin were observed following administration of CPX-351 versus non-liposomal (free) combination of cytarabine/daunorubicin. These findings provide insights into the safety and efficacy profiles observed for CPX-351 versus free cytarabine/daunorubicin in clinical studies. [Display omitted]