Publications by authors named "Mototsugu Ito"

6 Publications

  • Page 1 of 1

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

Muscle Nerve 2021 Oct 12. Epub 2021 Oct 12.

Parexel International, Baltimore, MD, USA.

Introduction/aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates PPARδ to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. Objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo; study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.

Results: A total of 64 (single dose cohort) and 37 (multiple dose cohort) participants were included. Following single doses of 1-120 mg, ASP0367 was rapidly absorbed with median time to maximum plasma concentration (t ) of 1.50-2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, t was delayed 1.7 hours. Following multiple once-daily doses, mean half-life of ASP0367 10-75 mg ranged from 14.1-17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed following repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild-to-moderate in severity; none were deemed drug-related. No clinically significant changes were observed on laboratory or electrocardiography evaluations. Treatment- and dose-dependent upregulation of six PPARδ target genes were observed with single and multiple doses of ASP0367.

Discussion: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.
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October 2021

Efficacy and safety of a 3-month dosing regimen of degarelix in Japanese patients with prostate cancer: a phase II maintenance-dose-finding study.

Jpn J Clin Oncol 2017 May;47(5):438-446

Strategic Investigation on Comprehensive Cancer Network, The University of Tokyo, Tokyo, Japan.

Objective: To evaluate the efficacy and safety of degarelix 3-month depot in Japanese patients with prostate cancer.

Methods: In this Phase II, open-label, parallel-group study, 155 Japanese prostate cancer patients were randomized to treatment with degarelix administered subcutaneously at a maintenance dose of 360 or 480 mg every 84 days for 12 months, after receiving an initial dose of 240 mg. The primary endpoint was the cumulative probability of serum testosterone ≤0.5 ng/ml (Days 28-364). Secondary endpoints included percent change in serum prostate-specific antigen level and proportion of patients with prostate-specific antigen failure at Day 364. For safety, adverse events were evaluated.

Results: The cumulative probability of serum testosterone ≤0.5 ng/ml (Days 28-364) was 88.3% (95% confidence interval: 77.9-94.0%) and 97.2% (95% confidence interval: 89.4-99.3%) in the 360 and 480 mg groups, respectively. The median percent change in serum prostate-specific antigen level from baseline to Day 364 was -95.05% and -96.43% in the 360 and 480 mg groups, respectively; the proportion of patients with prostate-specific antigen failure was 2.7% and 1.3%. The most frequent adverse event was injection site reaction; however, this did not cause any patient to discontinue treatment.

Conclusions: The 3-month dosing regimen of degarelix 360/480 mg was effective and well tolerated for treatment of Japanese prostate cancer patients. The 480 mg group showed a higher cumulative castration rate than the 360 mg group; thus, 480 mg was considered to be the optimal clinical dosage for future Phase III trials.
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May 2017

Pharmacokinetic Modeling and Monte Carlo Simulation to Predict Interindividual Variability in Human Exposure to Oseltamivir and Its Active Metabolite, Ro 64-0802.

AAPS J 2017 01 31;19(1):286-297. Epub 2016 Oct 31.

Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan.

Oseltamivir (Tamiflu®) is a prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. There is a possible relationship between oseltamivir treatment and neuropsychiatric adverse events; although this has not been established, close monitoring is recommended on the prescription label. The objective of this study was to predict interindividual variability of human exposure to oseltamivir and its active metabolite Ro 64-0802. By leveraging mathematical models and computations, physiological parameters in virtual subjects were generated with population means and coefficient of variations collected from the literature or produced experimentally. Postulated functional changes caused by genetic mutations in four key molecules, carboxylesterase 1A1, P-glycoprotein, organic anion transporter 3, and multidrug resistance-associated protein 4, were also taken into account. One hundred thousand virtual subjects were generated per simulation, which was iterated 20 times with different random number generator seeds. Even in the most exaggerated case, the systemic areas under the concentration-time curve (AUCs) of oseltamivir and Ro 64-0802 were increased by at most threefold compared with the population mean. By contrast, the brain AUCs of oseltamivir and Ro 64-0802 were increased up to about sevenfold and 40-fold, respectively, compared with the population means. This unexpectedly high exposure to oseltamivir or Ro 64-0802, which occurs extremely rarely, might trigger adverse central nervous system effects in the clinical setting.
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January 2017

Evaluation of [(11)C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection.

EJNMMI Res 2014 2;4:24. Epub 2014 Jul 2.

Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.

Background: Abnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu®, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [(11)C]oseltamivir was quantitatively evaluated in juvenile monkeys.

Methods: Three 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [(11)C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [(11)C]oseltamivir kinetics. Brain uptake of [(11)C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured.

Results: Plasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [(11)C]oseltamivir were 0.0033 and 0.0035% ID/cm(3) × kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051 mL/min/cm(3) for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable.

Conclusions: The brain uptake of [(11)C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.
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July 2014

Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4).

Drug Metab Dispos 2009 Feb 24;37(2):315-21. Epub 2008 Nov 24.

Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

[3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802) is a pharmacologically active form of the anti-influenza virus drug oseltamivir. Abnormal behavior is a suspected adverse effect of oseltamivir on the central nervous system. This study focused on the transport mechanisms of Ro 64-0802 across the blood-brain barrier (BBB). Ro 64-0802 was found to be a substrate of organic anion transporter 3 (OAT3/SLC22A8) and multidrug resistance-associated protein 4 (MRP4/ABCC4). Human embryonic kidney 293 cells expressing OAT3 exhibited a greater intracellular accumulation of Ro 64-0802 than mock-transfected cells (15 versus 1.2 microl/mg protein/10 min, respectively). The efflux of Ro 64-0802 was 3-fold greater when MRP4 was expressed in MDCKII cells and was significantly inhibited by indomethacin. After its microinjection into the cerebrum, the amount of Ro 64-0802 in brain was significantly greater in both Oat3(-/-) mice and Mrp4(-/-) mice compared with the corresponding wild-type mice (0.36 versus 0.080 and 0.32 versus 0.060 nmol at 120 min after injection, respectively). The brain/plasma concentration ratio (K(p,) (brain)) of Ro 64-0802, determined in wild-type mice after subcutaneous continuous infusion for 24 h, was close to the capillary volume (approximately 10 microl/g brain). Although the K(p,) (brain) of Ro 64-0802 was unchanged in Oat3(-/-) mice, it was significantly greater in Mrp4(-/-) mice (41 microl/g of brain). These results suggest that Ro 64-0802 can cross the BBB from the blood, but its brain distribution is limited by its active efflux by Mrp4 and Oat3 across the BBB. The transporter responsible for the brain uptake of Ro 64-0802 remains unknown, but Oat3 is a candidate transporter.
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February 2009

Phosphorylated PKR contributes the induction of GRP94 under ER stress.

Biochem Biophys Res Commun 2007 Aug 26;360(3):615-20. Epub 2007 Jun 26.

Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 13-0033, Japan.

Phosphorylated double-stranded RNA-dependent protein kinase (PKR) is thought to play an important role during ER stress induced cell death, but its molecular mechanism of action has not yet been clarified completely. To resolve this issue, we employed a PKR inhibitor together with ER stress inducers (tunicamycin, thapsigargin, and 2-deoxyglucose) and found that this treatment applied to SK-N-SH and HepG2 cells suppressed the expressional induction of 94kDa glucose regulated protein (GRP94) but not GRP78 proteins at both protein and mRNA levels. Although GRP94 mRNA increased, no significant difference was observed in the mRNA level of spliced X box binding protein 1 (XBP1) and reporter gene assay using GRP78 and GRP94 promoter with an ER stress response element (ERSE) showed that PKR inhibitor did not affect their activity. These results suggest that a novel mechanism other than ERSE-dependent mRNA transcription is required for the induction of GRP94 and phosphorylation of PKR contributes to the induction of GRP94 under ER stress.
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August 2007