Background: Activation of the mTOR signaling pathway is frequently observed in multiple types of cancer. The poor solubility and low oral bioavailability of the mTOR inhibitor sirolimus limit its development as an anticancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus developed with a proprietary nanoparticle albumin-bound (nab®) technology. Currently, numerous phase 1 and 2 clinical studies are ongoing with ABI-009, including a registrational phase 2 study for the treatment of malignant perivascular epithelioid cell carcinoma (PEComa), and various oncology (bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers) as well as in non-oncology indications (pulmonary arterial hypertension (PAH), pediatric epilepsy, and mitochondrial diseases). Several nonclinical studies were conducted to evaluate pharmacokinetics, tissue distribution and in particular, CNS penetration of ABI-009.

Methods: Rats were intravenously (IV) administered with a single dose of ABI-009 at 1.7, 9.5, and 17 mg/kg. Blood and organs were collected at 2, 8, 24, 72, and 120 hrs to analyze for sirolimus concentrations.

Results: There is a generally linear dose response with sirolimus concentrations in blood, heart, lung, liver, and pancreas following a single dose of IV ABI-009. Sirolimus concentrations in blood and well-perfused organs had high peaks at earlier time points but dropped quickly with time, with the highest concentrations observed in lung. In contrast, sirolimus concentrations in brain rose slowly at first, but maintained at a steady level over time. After 5 days, sirolimus level in the brain was similar to other organs, suggesting substantial and prolonged drug distribution to the brain with ABI-009. Organ/blood ratios of most organs increased with time, with the brain/blood ratios increasing more significantly over time. Higher initial dose of ABI-009 resulted in increased brain/blood ratios.

Conclusions: ABI-009 administered IV demonstrated a distinct PK profile compared with oral mTOR inhibitors. The PK of ABI-009 is characterized by higher Cmax and AUC, and rapid tissue distribution. Combined with efficient tumor penetration observed in a xenograft study, results of this study support the potential use of ABI-009 for the treatment of cancers in different organ sites, including lung, brain, liver, and pancreas. These findings also warrant further clinical studies in non-oncology indications including PAH and disorders involving the CNS.

Citation Format: Shihe Hou, Anita Schmid, Neil Desai. Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (nab-Sirolimus) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3896.