Integration of preclinical data to support the design of the first in-man study of LY2181308, a second generation antisense oligonucleotide.
Callies Sophie 1, Andre Valerie 2, Patel Bharvin 3, Waters David 4, Francis Paul 5, Lahn Michael 6, De Alwis Dinesh 7, Slapak Christopher 8.
1 2 7, Eli Lilly and Company, Windlesham UK ; 3,4,5,6,8 Eli Lilly and Company, Indianaplis USA.
Goals: Using preclinical data, the analysis aimed at predicting the concentration and target inhibition profile of the survivin-inhibitor and antisense oligonucleotide (ASO) LY2181308 in humans.
Methods: An indirect pharmacodynamic (PD) model describing survivin mRNA and protein inhibition in humans following LY2181308 dosing was built using preclinical target inhibition and tumor growth delay data from murine xenografts. Plasma and tissue pharmacokinetic (PK) data from monkey were analysed by non-linear mixed effect modeling technique (NONMEM V). Allometric scaling was used to predict PK parameters in humans. Clinical PK/PD profiles were simulated (Monte-Carlo simulations).
Results: The pre-clinical PK/PD model predicted LY2181308 tumor concentrations ranging from 18.8 to 54 µg/g and target inhibition from 50 to 90 % inhibition (5th-95th percentiles) following 750 mg of LY2181308 in humans. The clinical data showed LY2181308 tumor concentrations ranging from 13.9 to 52.8 µg/g (n=4 patients at 750 mg), with a median survivin mRNA and protein inhibition of 20 % +/- 34 (SD) (n=9) and 23 % +/- 63 (SD) (n=10), respectively. The human multi-compartmental PK parameters were: central Vd, 4.09 L (SEE 8.95%); distribution clearances, 2.54 (4.06%), 0.0608 (29.6%) and 1.67 (23.8%) L/h; Peripheral Vds, 25900 (16.3%), 0.936 (22.5%) and 2.51 (11.6%) L; mean elimination clearance 23.1 L/h; mean terminal half-life, 32.7 days (range 22-52 days). Although the PD effect was over-estimated, the PK parameters were well predicted (median difference between observed and predicted PK parameters value of 20 % range (1 to 55 %).
Conclusion: The integration of preclinical PK/PD data can help predict with reasonable accuracy the appropriate dose and dosing regimen of ASOs in humans.
