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Pharmacokinetic–pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice

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Abstract

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.

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Acknowledgments

The authors would like to thank Ms. Keiko Ogawa, Mr. Takanori Hironaka, Dr. Tatsuya Ikehara, Dr. Ken-ichi Nezasa, Mr. Shingo Sakamoto, and Dr. Shuichi Onishi (Drug Metabolism and Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd.) for their support during and discussion related to the animal experiments.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Japan

    Ryosuke Shimizu, Mikiko Kitade & Ayahisa Watanabe

  2. Biotechnology-Based Medicine, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Japan

    Shin-Ichiro Hori

  3. Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Sapporo, Japan

    Takashi Kobayashi

Authors
  1. Ryosuke Shimizu
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  2. Mikiko Kitade
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  3. Takashi Kobayashi
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  4. Shin-Ichiro Hori
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  5. Ayahisa Watanabe
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Corresponding author

Correspondence to Ayahisa Watanabe.

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Shimizu, R., Kitade, M., Kobayashi, T. et al. Pharmacokinetic–pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice. J Pharmacokinet Pharmacodyn 42, 67–77 (2015). https://doi.org/10.1007/s10928-014-9398-5

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  • DOI: https://doi.org/10.1007/s10928-014-9398-5

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