Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human Phase 1 studies

Although there are currently more than 30 antibody-drug conjugates (ADC) in clinical development for the treatment of blood cancers and solid tumors, comparison of their clinical pharmacokinetics (PK) is challenging because of the large number of, and differences between, the targets, ADC constructs...

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Bibliographic Details
Published inmAbs Vol. 6; no. 4; pp. 859 - 870
Main Author Deslandes, Antoine
Format Journal Article
LanguageEnglish
Published United States Taylor & Francis 01.07.2014
Landes Bioscience
Subjects
Antibodies, Monoclonal - pharmacokinetics
Antibodies, Monoclonal - therapeutic use
Antibodies, Neoplasm - therapeutic use
antibody-drug conjugates
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Clinical Trials, Phase I as Topic
dose selection
Dose-Response Relationship, Drug
dosing regimen
Female
Humans
Immunoconjugates - pharmacokinetics
Immunoconjugates - therapeutic use
Male
maximum tolerated dose
Neoplasms - drug therapy
Neoplasms - metabolism
oncology
pharmacokinetics
phase I
Review
maximum tolerated dose
pharmacokinetics
dose selection
phase I
antibody-drug conjugates
dosing regimen
oncology
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Summary:Although there are currently more than 30 antibody-drug conjugates (ADC) in clinical development for the treatment of blood cancers and solid tumors, comparison of their clinical pharmacokinetics (PK) is challenging because of the large number of, and differences between, the targets, ADC constructs, dosing regimens, and patient populations. In this review, we standardized the evaluation, using non-compartmental PK data reported at Cycle 1, i.e., following the first drug administration of what is usually a repeated-dose treatment, in monotherapy. We report ADC clinical PK properties, dosing regimen, determination of doses ranges and associated maximum tolerated doses. We also evaluated the effect of structural characteristics and target types (hematological vs. solid tumors) on PK. In addition, we discuss how integration of PK/pharmacodynamics approaches on top of classical dose escalation in first-in-human studies may improve dosing regimen determination for subsequent phases of clinical development.
ISSN:1942-0862
1942-0870
1942-0870
1942-0862
DOI:10.4161/mabs.28965