Biopharmaceutical

Biotechnology

Biology

Pharmacokinetics

Prodrug

Biochemistry

Drug

Drug discovery

Drug development

Pharmacology

Medicine

Chemistry

Nature Reviews Drug Discovery

Prodrug strategies can be used to overcome pharmacokinetic and pharmacodynamic issues in many therapeutic agents. Here, Rautio and colleagues discuss which approaches have been most successful, particularly in the past 10 years, and highlight the challenges in incorporating prodrug moieties during drug development. Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting. In the past 10 years, the US Food and Drug Administration has approved at least 30 prodrugs, which accounts for more than 12% of all approved small-molecule new chemical entities. In this Review, we highlight prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs. We also discuss preclinical and clinical challenges and considerations in prodrug design and development.

The expanding role of prodrugs in contemporary drug design and development