Microdosing imaging pharmacokinetic (PK) study of the antisense oligonucleotide (ASO) to survivin (LY2181308) using positron emission tomography (PET): A novel paradigm in clinical drug development

3578 Background: Survivin, an inhibitor of an apoptosis protein, widely overexpressed in cancer is associated with poor clinical outcome. We performed the first worldwide human microdosing imaging PK study of an ASO with LY2181308, a specific, second generation antisense inhibitor of Survivin using carbon-11 radiolabelled LY2181308 ([ 11 C]LY2181308). Methods: LY2181308 was administered at the recommended phase II dose (750 mg over 3 hours IV daily x 3, then once weekly). [ 11 C]LY2181308 was manufactured to GMP standard by random [ 11 C]methylation with [ 11 C]methyl iodide of LY2181308 using a GE Tracerlab FXc molecule. [ 11 C]LY2181308-PET scans were performed at baseline and during treatment infusion. [ 11 C]LY2181308 uptake in normal tissue and tumour was quantified. Results: Three pts (2 female Caucasian/1 male Asian) were scanned after administering [ 11 C]LY2181308 which delivered (135–376 μg) of LY2181308. Despite its large size (6778 amu), [ 11 C]LY2181308 rapidly distributed to tissues, with maximal uptake in kidney followed by liver, spleen, vertebral body, tumour, spinal cord, lung, and muscle at baseline. Although renal uptake was high, urinary elimination (bladder activity) was low suggesting renal trapping of [ 11 C]LY2181308 at baseline. For a normalised injected dose of 1 mg, mean (range) tumour concentrations of 31 (4–41) ng/ml were observed at baseline, consistent with that predicted from the preclinical PK/PD model. In a pt with mesothelioma who also had a second [ 11 C]LY2181308-PET scan during LY2181308 treatment infusion, there was about 2-fold increase in [ 11 C]LY2181308 tumour uptake, in contrast to markedly reduced uptake in kidneys, liver, and spleen and similar aortic (circulatory) [ 11 C]LY2181308 levels. In this patient, tumour [ 18 F]FDG- PET uptake at 28 days was reduced by up to 40% after treatment, suggesting drug activity. Conclusions: [ 11 C]LY2181308 pharmacokinetics suggest biologically active human tumour drug concentrations can be attained. LY2181308 therapy saturated normal tissue kinetics and increased tumour uptake of [ 11 C]LY2181308. Data uniquely obtained from fully regulated microdosing studies may rationalise and hasten drug development. [Table: see text]