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.
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The authors' research on prodrugs was funded by the Academy of Finland (grant number 308329 to J.R.). The authors also want to recognize C. McGuigan (1958–2016) for his outstanding achievements in prodrug research, which paved the way for the development of phosphoramidate ProTide phosphate and phosphonate prodrug technology.
The authors declare no competing financial interests.
- Solid form selection
The selection and characterization of the preferred pharmaceutical solid-state form of a drug.
The combination of excipients with the active pharmaceutical ingredient.
- Dosage form design
A formulation configured to provide a particular delivery function via a commercializable format.
A covalently bound, inactive moiety bound to a drug to form a prodrug that provides the desired pharmaceutical properties.
Administered via skin penetration (typically intravenous, subcutaneous or intramuscular).
A drug effective against vomiting and nausea.
- Oral bioavailability
The fraction of orally dosed drug that reaches the systemic circulation.
Substances added to formulations to improve delivery or efficacy.
- ProTide-based prodrugs
The ProTide technology is most commonly used to deliver nucleotide analogues to cells. The hydroxyls of the monophosphate or monophosphonate are masked by an aromatic group and an amino acid ester.
- First-pass effect
An effect in which the concentration of a drug is greatly reduced via presystemic metabolism before it reaches the systemic circulation.
The distribution of a drug throughout the body following administration.
- Parietal cells
Epithelial cells lining the stomach that secrete hydrogen chloride.
The transport of fluid into a cell via vesicles created by local infoldings by the cell membrane.
- Ussing chamber
A perfusion device used to measure transport across epithelial membranes.
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Rautio, J., Meanwell, N., Di, L. et al. The expanding role of prodrugs in contemporary drug design and development. Nat Rev Drug Discov 17, 559–587 (2018). https://doi.org/10.1038/nrd.2018.46
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