Safety, tolerability, and pharmacokinetics of NK-104-NP a multicenter, randomized, placebo-controlled phase I investigator-initiated trial for intravenous administration of pitavastatin-loaded plga nanoparticles (Nk-104-NP) in healthy Japanese male subjects

Kaku Nakano, Tetsuya Matoba, Jun Ichiro Koga, Yushi Kashihara, Masato Fukae, Ichiro Ieiri, Masanari Shiramoto, Shin Irie, Junji Kishimoto, Koji Todaka, Kensuke Egashira

研究成果: ジャーナルへの寄稿記事

2 引用 (Scopus)

抄録

Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached Cmax (the maximum drug concentration) in all groups. Cmax, AUC0-t (area under the curve from time 0 to the last measurable concentration) and AUC0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean Cmax and AUC0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.

元の言語英語
ページ(範囲)1015-1025
ページ数11
ジャーナルInternational heart journal
59
発行部数5
DOI
出版物ステータス出版済み - 1 1 2018

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Intravenous Administration
Nanoparticles
Pharmacokinetics
Placebos
Research Personnel
Safety
Healthy Volunteers
Pulmonary Hypertension
Area Under Curve
pitavastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Clinical Trials, Phase I
Nanotechnology
Pharmaceutical Preparations
Pulmonary Artery
Anti-Inflammatory Agents
Medicine
Clinical Trials
Calcium
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

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title = "Safety, tolerability, and pharmacokinetics of NK-104-NP a multicenter, randomized, placebo-controlled phase I investigator-initiated trial for intravenous administration of pitavastatin-loaded plga nanoparticles (Nk-104-NP) in healthy Japanese male subjects",
abstract = "Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached Cmax (the maximum drug concentration) in all groups. Cmax, AUC0-t (area under the curve from time 0 to the last measurable concentration) and AUC0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean Cmax and AUC0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.",
author = "Kaku Nakano and Tetsuya Matoba and Koga, {Jun Ichiro} and Yushi Kashihara and Masato Fukae and Ichiro Ieiri and Masanari Shiramoto and Shin Irie and Junji Kishimoto and Koji Todaka and Kensuke Egashira",
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AU - Nakano, Kaku

AU - Matoba, Tetsuya

AU - Koga, Jun Ichiro

AU - Kashihara, Yushi

AU - Fukae, Masato

AU - Ieiri, Ichiro

AU - Shiramoto, Masanari

AU - Irie, Shin

AU - Kishimoto, Junji

AU - Todaka, Koji

AU - Egashira, Kensuke

PY - 2018/1/1

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