Mechanistic PKPD Models of Protein Therapeutics for Early Clinical Development


Mechanistic PKPD models support FIH trial design, development of targeted immunotherapies, and understanding complex PK properties and covariates. 

The modern pharmaceutical industry was borne out of organic chemistry, and thus most drugs in use today consist of chemically synthesized small molecules. Advances in biotechnology and protein engineering over the last few decades have, however, ushered in a new wave of drug modalities. While the first monoclonal antibody was approved as a therapeutic agent just over 30 years ago, these now constitute more than 25 percent of new drug approvals.1 Many protein-based drugs with novel structures and mechanisms of action are now in clinical development and on the market, such as immune-modulators for oncology, bispecifics, single-chain antibodies, and antibody-drug conjugates.

Compared to small molecules, protein-based therapeutics typically possess much higher target specificity and potency (often binding affinity in the pM-range). Due to the high specificity, the toxicities more often arise from exaggerated pharmacology or on-target activity.


Fei Hua, Ph.D.; Daniel Kirouac, Ph.D.; Lore Gruenbaum, Ph.D.; John Burke, Ph.D.; Joshua Apgar, Ph.D. (2018). 

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