Evaluating physiochemical properties of FDA-approved orally administered drugs

ABSTRACT

Introduction

Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski’s Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs.

Areas Covered

The authors noted that a significant proportion of FDA-approved orally administered parent compounds from 2011 to 2022 deviate from the original Ro5 criteria (~38%) or the Ro5 with extensions (~53%). They then evaluated if a contemporary Ro5 criteria (cRo5) could be devised to better predict oral bioavailability. Furthermore, they discuss many case studies showcasing the need for and benefit of increasing the size of certain compounds and cover several evolving strategies for improving oral bioavailability.

Expert opinion

Despite many revisions to the Ro5, the authors find that no single proposed physiochemical rule has universal concordance with absolute oral bioavailability. Innovations in drug delivery and formulation have dramatically expanded the range of physicochemical properties and the chemical diversity for oral administration.

KEYWORDS:

• Drug development
• drug discovery
• Lipinski’s Rule of Five
• oral formulation
• FDA approval
• beyond Ro5
• oral bioavailability

Article highlights

• A significant portion of contemporary FDA-approved drugs do not follow Lipinski’s Rule of Five (Ro5) or the Extended Rule of Five (eRo5) rulesets.

• No single physiochemical rule has any correlation with absolute oral bioavailability.

• Most common rule violated is the MW cutoff in the Ro5 and larger compounds may be necessary to better bind some molecular targets.

• Updated rulesets including a contemporary Ro5 (cRo5) are insufficient to define all orally bioavailable drugs.

• Evolving formulation approaches continue to expand the range of compounds that can be administered orally.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460441.2023.2275617

Additional information

Funding

The authors are funded by the Mimi and John A Cole Research Foundation.