Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide
S Callies, V André, B Patel, D Waters… - British journal of …, 2011 - Wiley Online Library
S Callies, V André, B Patel, D Waters, P Francis, M Burgess, M Lahn
British journal of clinical pharmacology, 2011•Wiley Online LibraryWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The plasma pharmacokinetics (PK) of
second generation antisense oligonucleotides (ASOs) are fairly well understood with well
conserved pharmacokinetic properties across species, moderate clearance and extensive
volume of distribution. WHAT THIS STUDY ADDS• The tissue distribution and exposure and
the pharmacodynamic (PD) or target inhibition following ASO administration are not yet well
understood leading to still fairly empiric early clinical development strategies. This paper …
second generation antisense oligonucleotides (ASOs) are fairly well understood with well
conserved pharmacokinetic properties across species, moderate clearance and extensive
volume of distribution. WHAT THIS STUDY ADDS• The tissue distribution and exposure and
the pharmacodynamic (PD) or target inhibition following ASO administration are not yet well
understood leading to still fairly empiric early clinical development strategies. This paper …
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The plasma pharmacokinetics (PK) of second generation antisense oligonucleotides (ASOs) are fairly well understood with well conserved pharmacokinetic properties across species, moderate clearance and extensive volume of distribution.
WHAT THIS STUDY ADDS
• The tissue distribution and exposure and the pharmacodynamic (PD) or target inhibition following ASO administration are not yet well understood leading to still fairly empiric early clinical development strategies. This paper illustrates how preclinical PK and PD data were used to predict more accurately the ASO tissue exposure in humans and to support the early clinical development strategy.
AIMS To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans.
METHODS An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non‐linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles.
RESULTS Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54 µg g−1 were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations from 13.9 to 52.8 µg g−1 (n = 4, LY2181308 750 mg) were observed associated with a median survivin mRNA and protein inhibition of 20% ± 34 (SD) (n = 9) and 23% ± 63 (SD) (n = 10), respectively. The human PK parameters were adequately estimated: central Vd, 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00) l h−1, peripheral Vds, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922) l, mean elimination clearance 23.1 l h−1 (5.6, 33.4) and mean terminal half‐life, 32.7 days (range 22–52 days).
CONCLUSION The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750 mg.
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