Pharmacokinetic-pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice.
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 81-183 h, Tmax: 0.25-0.50 and 4-8 h). After administration, hepatic Apo-B mRNA and plasma total cholesterol began decreasing at 4-8 and 8-24 h, and their Tmax values were observed at 24-72 and 72 h. 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.
Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan.
Ryosuke
R
Shimizu
Mikiko
M
Kitade
Takashi
T
Kobayashi
Shin-Ichiro
S
Hori
Ayahisa
A
Watanabe
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood*; D003198:Computer Simulation; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D013997:Time Factors
C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D002784:Cholesterol