Safety, Tolerability, and Pharmacodynamics of Intrathecal Injection of Recombinant Human HGF (KP‐100) in Subjects With Amyotrophic Lateral Sclerosis: A Phase I Trial

Hepatocyte growth factor is an endogenous pleiotropic factor shown to act as a potent neuroprotectant against disease progression in animal models of amyotrophic lateral sclerosis, which is a devastating, adult‐onset motor neuron disease. To evaluate the safety, tolerability, and pharmacokinetics of...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2019-05, Vol.59 (5), p.677-687
Main Authors: Warita, Hitoshi, Kato, Masaaki, Asada, Ryuta, Yamashita, Atsuko, Hayata, Daichika, Adachi, Kiichi, Aoki, Masashi
Format: Article
Language:English
Subjects:
ALS
Amyotrophic lateral sclerosis
Animal diseases
Animal models
Central nervous system
Central nervous system diseases
Cerebrospinal fluid
Dosage
Growth factors
Hepatocyte growth factor
Injection
intrathecal
Malfunctions
Medical instruments
Motor neuron diseases
Neuroprotective agents
Pharmacodynamics
Pharmacokinetics
phase I
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Summary:Hepatocyte growth factor is an endogenous pleiotropic factor shown to act as a potent neuroprotectant against disease progression in animal models of amyotrophic lateral sclerosis, which is a devastating, adult‐onset motor neuron disease. To evaluate the safety, tolerability, and pharmacokinetics of recombinant 5‐residue‐deleted human hepatocyte growth factor (KP‐100) injected intrathecally through an implantable catheter connected to a subcutaneous port, we conducted a first‐in‐human phase I trial of intrathecal KP‐100 in 15 Japanese patients with amyotrophic lateral sclerosis. The regimen was a single injection of 3 escalating doses (0.2, 0.6, and 2.0 mg/body) in 9 subjects followed by 2 doses (0.6 and 2.0 mg/body) repeated 5 times at 1‐week intervals in 6 subjects (3 subjects/group). With single‐dose administration, the mean half‐life of KP‐100 in the cerebrospinal fluid was 1.2 to 1.4 days, with its maximum concentration increasing in a dose‐dependent manner. With multiple‐dose administration, the trough KP‐100 concentrations in the cerebrospinal fluid generally remained constant for any dose, despite multiple dosing. There were no deaths, serious adverse events, or device malfunctions leading to discontinuation. In all subjects, plasma KP‐100 concentrations were
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.1355