Drug safety evaluation through biomarker analysis-A toxicity study in the cynomolgus monkey using an antibody-cytotoxic conjugate against ovarian cancer

Journal Article · Mon Oct 01 00:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.06.009· OSTI ID:21077808

Tengstrand, Elizabeth ^[1]; Lee, J -W; Li, Lily Y; Silverman, Lee; Riordan, Bill ^[2]; Miwa, Gerald ^[1]; Milton, Mark; Alden, Carl; Lee, Frank ^[2]

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1. Nextcea, Inc., 110 Hartwell Avenue, Lexington, MA 02421 (United States)
2. Millennium Pharmaceuticals, Inc., 35 Lansdowne Street, Cambridge, MA 02139 (United States)

Antibody-cytotoxin conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify serum biomarkers that correlate with MLN8866 (an Antibody-Cytotoxic Conjugate, mAb8866-CT) pathological events in monkeys and to predict the maximal tolerated dose (MTD) level using biomarkers. Cynomolgus monkeys were administered a single dose MLN8666 (5, 15 or 30 mg/kg) by intravenous infusion and evaluated over a 7-day period. Exposure levels were determined by quantifying MLN8866 levels (C{sub max} and AUC{sub 0-96h}) in serum. The increase in MLN8866 C{sub max} and AUC{sub 0-96h} was approximately dose proportional. Two biomarkers in serum (m/z 316 and m/z 368) were identified to be correlated with MLN8866 toxicological outcomes. The predicted MTD, 11.4 mg/kg, was within the MTD range set by pathology results (5-15 mg/kg). Administration of MLN8866 at 15 mg/kg and 30 mg/kg dose levels resulted in changes in hematology parameters associated with impaired hematopoiesis and bone marrow toxicity. The projected MLN8866 MTD exposure level was integrated with toxicokinetic analysis and showed C{sub max} = 236 {mu}g/mL and AUC{sub 0-96h} = 7246 h mg/mL. The safety of three different MLN8866 dosing regimens with three dosing schedules was explored with pharmacokinetic modeling.

• OSTI ID: 21077808
• Journal Information: Toxicology and Applied Pharmacology, Vol. 224, Issue 1; Other Information: DOI: 10.1016/j.taap.2007.06.009; PII: S0041-008X(07)00267-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
BIOLOGICAL MARKERS
BLOOD FORMATION
BONE MARROW
DOSES
DRUGS
HEMATOLOGY
INFUSION
MONKEYS
NEOPLASMS
PATHOLOGY
SAFETY ANALYSIS
TOXICITY
TOXINS