ArticleThe AAPS journal2011
From target selection to the minimum acceptable biological effect level for human study: use of mechanism-based PK/PD modeling to design safe and efficacious biologics.
Article in The AAPS journal, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed.
- A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers.Antimicrobial agents and chemotherapy · 2016Trial
- AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies.CPT: pharmacometrics & systems pharmacology · 2017Article
- A Tutorial on Target-Mediated Drug Disposition (TMDD) Models.CPT: pharmacometrics & systems pharmacology · 2015Article
- Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases.Pharmacology research & perspectives · 2015Article
- Factors influencing magnitude and duration of target inhibition following antibody therapy: implications in drug discovery and development.The AAPS journal · 2013Article
- Clinical pharmacology considerations in biologics development.Acta pharmacologica Sinica · 2012Review
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Corrections and comments
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Authors and funding
4 authors.
Funding
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Abstract
In this paper, two applications of mechanism-based modeling are presented with their utility from candidate selection to first-in-human dosage selection. The first example is for a monoclonal antibody against a cytomegalovirus glycoprotein complex, which involves an antibody binding model and a viral load model. The model was used as part of a feasibility analysis prior to antibody generation, setting the specifications for the affinity needed to achieve a desired level of clinical efficacy. The second example is a pharmacokinetic-pharmacodynamic model based on a single-dose pharmacology study in cynomolgus monkey using data on pharmacokinetics, receptor occupancy, and the dynamics of target cell depletion and recovery. The model was used to estimate the MABEL, here defined as the minimum acceptable biological effect level against which a dose is selected for a first-in-human study. From these applications, we demonstrate that mechanism-based PK/PD binding models are useful for predicting human response to biologics compounds. Especially, such models have the ability to integrate preclinical and clinical, in vitro and in vivo information and facilitate rational decision making during various stages of drug discovery and translational research.
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Registered trials
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