Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody: A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study

Hiroko Tabuchi, Toshinori Katsurabara, Masahiko Mori, Muneo Aoyama, Takashi Obara, Nobuyuki Yasuda, Tetsu Kawano, Toshio Imai, Ichiro Ieiri, Yuji Kumagai

Research output: Contribution to journalArticle

Abstract

E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double-blind, placebo-controlled single-ascending-dose study of intravenous administration of E6011 (0.0006-10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x-rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti-E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 μg/mL, identified as the minimum concentration needed to saturate the target-mediated elimination pathway. Model-based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.

Original languageEnglish
Pages (from-to)688-701
Number of pages14
JournalJournal of Clinical Pharmacology
Volume59
Issue number5
DOIs
Publication statusPublished - May 1 2019

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Pharmacokinetics
Monoclonal Antibodies
Placebos
Safety
Serum
Cholangitis
Macaca fascicularis
Vital Signs
Intravenous Infusions
Crohn Disease
Intravenous Administration
Anti-Idiotypic Antibodies
Rheumatoid Arthritis
Healthy Volunteers
Electrocardiography
Thorax
X-Rays
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody : A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study. / Tabuchi, Hiroko; Katsurabara, Toshinori; Mori, Masahiko; Aoyama, Muneo; Obara, Takashi; Yasuda, Nobuyuki; Kawano, Tetsu; Imai, Toshio; Ieiri, Ichiro; Kumagai, Yuji.

In: Journal of Clinical Pharmacology, Vol. 59, No. 5, 01.05.2019, p. 688-701.

Research output: Contribution to journalArticle

Tabuchi, Hiroko ; Katsurabara, Toshinori ; Mori, Masahiko ; Aoyama, Muneo ; Obara, Takashi ; Yasuda, Nobuyuki ; Kawano, Tetsu ; Imai, Toshio ; Ieiri, Ichiro ; Kumagai, Yuji. / Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody : A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study. In: Journal of Clinical Pharmacology. 2019 ; Vol. 59, No. 5. pp. 688-701.
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