Abstract A137: Utilization of preclinical xenograft data in predicting human imetelstat target tissue concentrations.

Abstract

Abstract Purpose: Imetelstat is a first-in-class, lipidated 13-mer oligonucleotide thio-phosphoramidate telomerase inhibitor with anti-tumor activity. It is currently in Phase II clinical development. Its distribution in tissues, specifically tumor and bone marrow, was studied in a xenograft mouse model established using a human OVCAR-5 cell line. Data from the xenograft study indicated imetelstat tumor and bone marrow concentrations were sustained during the terminal phase. This suggests further study of imetelstat distribution in human tumor and bone marrow will be important in order to facilitate clinical understanding of drug concentration in the target tissues of hematological and solid tumor malignancies. Due to clinical sampling difficulties of these tissues, we aimed to develop a target tissue pharmacokinetic model to simulate imetelstat human tumor and bone marrow concentrations based on patient plasma levels. Experimental Design: Nude mice each received a tumor challenge of 3 million OVCAR-5 cells injected subcutaneously into contralateral flanks. Animals were randomized into 15 and 30 mg/kg treatment groups when tumors reached ∼200 mm3 in size, and were treated with imetelstat 3 times a week via IP bolus injection. Plasma, tumor and bone marrow samples were harvested at various time points post last drug treatment. Samples were subjected to a novel extraction procedure using a biotinylated capture probe before imetelstat concentration determination with ion-pairing reversed-phase LC/MS/MS. Human plasma data was obtained from solid tumor patients in a Phase I clinical trial after a 2-hr IV infusion of imetelstat at 9.4 mg/kg. Results: Imetelstat concentrations in plasma, tumor and bone marrow were quantified in xenograft mouse samples. Imetelstat distributes rapidly into bone marrow, and with a slight delay into the tumor tissue. For the 30 mg/kg dose group, based on preliminary data, imetelstat concentrations were determined up to 36 and 48 hrs in bone marrow and tumor, respectively, with 0.61 ug/mL in bone marrow and 1.05 ug/g in tumor. Concentrations in bone marrow and tumor were at higher levels than that in plasma when an equilibrium was established after 24 hrs following distribution between tissue and plasma. Tissue:plasma ratio during the terminal phase approximates 60 in bone marrow and 190 in tumor. This dataset was used in building a preclinical pharmacokinetic model to describe imetelstat tissue distribution in xenograft mouse. Imetelstat concentration time profiles in plasma and tissue were modeled simultaneously. Plasma profile was described by a two compartment open model, while tissue profiles were modeled with a first order transfer from central to tissue compartment. Using this model, together with human plasma data at 9.4 mg/kg, imetelstat tissue concentration profiles in human tumor and bone marrow were simulated. Conclusions: A target tissue pharmacokinetic model was established to describe imetelstat tumor and bone marrow distribution profiles in xenograft mouse. This model was applied toward the modeling and prediction of imetelstat target tissue concentrations in patients, and may be used to guide clinical trial dosing and dosing regimen(s). Detailed results of modeling and clinical implications will be determined when confirmatory studies are completed and will be presented at the meeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A137.