caa a22 4500 605533733 CHVBK 20210128100839.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s10928-014-9398-5 doi (NATIONALLICENCE)springer-10.1007/s10928-014-9398-5 Pharmacokinetic-pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice [Elektronische Daten] [Ryosuke Shimizu, Mikiko Kitade, Takashi Kobayashi, Shin-Ichiro Hori, Ayahisa Watanabe] Second-generation antisense oligonucleotides (ASOs) demonstrate excellent biological stability and in vitro/in vivo potency, and thus are considered to be attractive candidates for drugs to treat various diseases. A pharmacokinetic-pharmacodynamic (PK-PD) model of ASOs is desired for the design of appropriate PK and pharmacological studies. The objective of this study was to develop a PK-PD model to accurately simulate hepatic ASO concentration and its efficacy from plasma ASO concentration. After single subcutaneous administration of an ASO targeting hepatic apolipoprotein B (Apo-B) mRNA to mice, the ASO was absorbed rapidly and showed biphasic decline with time from the plasma and liver (t1/2: 1-3 and 81-183h, Tmax: 0.25-0.50 and 4-8h). After administration, hepatic Apo-B mRNA and plasma total cholesterol began decreasing at 4-8 and 8-24h, and their Tmax values were observed at 24-72 and 72h. To develop the PK-PD model based on the mechanisms of ASOs, we described the plasma and hepatic ASO concentration with linear two-compartment models. In addition, we inserted two indirect response models for mRNA and plasma total cholesterol. Model predictions from plasma ASO concentration gave excellent fits to the observed values of hepatic ASO concentration, Apo-B mRNA and plasma total cholesterol after single or multiple subcutaneous administrations. Our PK-PD model could accurately predict hepatic ASO concentrations and their efficacies from plasma ASO concentrations. This PK-PD model could be a useful tool for suggesting PK and pharmacological study protocols for various liver-targeted second-generation ASOs. Springer Science+Business Media New York, 2014 PK-PD model nationallicence Antisense oligonucleotides nationallicence Apolipoprotein B nationallicence Time-delay nationallicence Shimizu Ryosuke Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan aut Kitade Mikiko Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan aut Kobayashi Takashi Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Sapporo, Japan aut Hori Shin-Ichiro Biotechnology-Based Medicine, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Japan aut Watanabe Ayahisa Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/1(2015-02-01), 67-77 1567-567X 42:1<67 2015 42 10928 https://doi.org/10.1007/s10928-014-9398-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-014-9398-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shimizu Ryosuke Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan aut NATIONALLICENCE 700 1- Kitade Mikiko Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan aut NATIONALLICENCE 700 1- Kobayashi Takashi Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Sapporo, Japan aut NATIONALLICENCE 700 1- Hori Shin-Ichiro Biotechnology-Based Medicine, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Japan aut NATIONALLICENCE 700 1- Watanabe Ayahisa Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/1(2015-02-01), 67-77 1567-567X 42:1<67 2015 42 10928