PMID- 30158384
OWN - NLM
STAT- MEDLINE
DCOM- 20181009
LR  - 20181009
IS  - 1349-3299 (Electronic)
IS  - 1349-2365 (Linking)
VI  - 59
IP  - 5
DP  - 2018 Sep 26
TI  - Safety, Tolerability, and Pharmacokinetics of NK-104-NP.
PG  - 1015-1025
LID - 10.1536/ihj.17-555 [doi]
AB  - 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 C(max) (the 
      maximum drug concentration) in all groups. C(max), AUC(0-t) (area under the curve 
      from time 0 to the last measurable concentration) and AUC(0-infinity) (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 C(max) and 
      AUC(0-infinity) 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.
FAU - Nakano, Kaku
AU  - Nakano K
AD  - Department of Cardiovascular Research, Development, and Translational Medicine, 
      Center for Disruptive Cardiovascular Medicine, Kyushu University.
FAU - Matoba, Tetsuya
AU  - Matoba T
AD  - Department of Cardiovascular Medicine, Kyushu University Graduate School of 
      Medical Sciences.
FAU - Koga, Jun-Ichiro
AU  - Koga JI
AD  - Department of Cardiovascular Research, Development, and Translational Medicine, 
      Center for Disruptive Cardiovascular Medicine, Kyushu University.
AD  - Department of Cardiovascular Medicine, Kyushu University Graduate School of 
      Medical Sciences.
FAU - Kashihara, Yushi
AU  - Kashihara Y
AD  - Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical 
      Sciences, Kyushu University.
FAU - Fukae, Masato
AU  - Fukae M
AD  - Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical 
      Sciences, Kyushu University.
FAU - Ieiri, Ichiro
AU  - Ieiri I
AD  - Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical 
      Sciences, Kyushu University.
FAU - Shiramoto, Masanari
AU  - Shiramoto M
AD  - Souseikai Hakata Clinic.
FAU - Irie, Shin
AU  - Irie S
AD  - Souseikai Hakata Clinic.
FAU - Kishimoto, Junji
AU  - Kishimoto J
AD  - Center for Clinical and Translational Research, Kyushu University Hospital.
FAU - Todaka, Koji
AU  - Todaka K
AD  - Center for Clinical and Translational Research, Kyushu University Hospital.
FAU - Egashira, Kensuke
AU  - Egashira K
AD  - Department of Cardiovascular Research, Development, and Translational Medicine, 
      Center for Disruptive Cardiovascular Medicine, Kyushu University.
AD  - Department of Cardiovascular Medicine, Kyushu University Graduate School of 
      Medical Sciences.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20180829
PL  - Japan
TA  - Int Heart J
JT  - International heart journal
JID - 101244240
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Quinolines)
RN  - M5681Q5F9P (pitavastatin)
SB  - IM
MH  - Administration, Intravenous
MH  - Adult
MH  - Drug Delivery Systems
MH  - Healthy Volunteers
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & 
      dosage/*pharmacokinetics/therapeutic use
MH  - Hypertension, Pulmonary/*drug therapy/mortality/pathology
MH  - Japan/epidemiology
MH  - Lung/*blood supply/drug effects/pathology
MH  - Male
MH  - Nanotechnology/methods
MH  - Pulmonary Artery/drug effects
MH  - Quinolines/administration & dosage/blood/*pharmacokinetics/therapeutic use
OTO - NOTNLM
OT  - Drug delivery system
OT  - Nanotechnology
OT  - Phase I clinical trial
OT  - Population pharmacokinetic analysis
OT  - Pulmonary hypertension
OT  - Statin
EDAT- 2018/08/31 06:00
MHDA- 2018/10/10 06:00
CRDT- 2018/08/31 06:00
PHST- 2018/08/31 06:00 [pubmed]
PHST- 2018/10/10 06:00 [medline]
PHST- 2018/08/31 06:00 [entrez]
AID - 10.1536/ihj.17-555 [doi]
PST - ppublish
SO  - Int Heart J. 2018 Sep 26;59(5):1015-1025. doi: 10.1536/ihj.17-555. Epub 2018 Aug 
      29.