An update on the importance of plasma protein binding in drug discovery and development

ABSTRACT

Introduction: Plasma protein binding (PPB) remains a controversial topic in drug discovery and development. Fraction unbound (f_u) is a critical parameter that needs to be measured accurately, because it has significant impacts on the predictions of drug-drug interactions (DDI), estimations of therapeutic indices (TI), and developments of PK/PD relationships.  However, it is generally not advisable to change PPB through structural modifications, because PPB on its own has little relevance for in vivo efficacy.

Areas covered: PPB fundamentals are discussed including the three main classes of drug binding proteins (i.e., albumin, alpha1-acid glycoprotein, and lipoproteins) and their physicochemical properties, in vivo half-life, and synthesis rate.  State-of-the-art methodologies for PPB are highlighted. Applications of PPB in drug discovery and development are presented.

Expert opinion: PPB is an old topic in pharmacokinetics, but there are still many misconceptions. Improving the accuracy of PPB for highly bound compounds is an ongoing effort in the field with high priority. As the field continues to generate high quality data, the regulatory agencies will increase their confidence in our ability to accurately measure PPB of highly bound compounds, and experimental fu values below 0.01 will more likely be used for DDI predictions in the future.

KEYWORDS:

• Plasma protein binding
• fraction unbound
• equilibrium dialysis
• ultracentrifugation
• albumin
• alpha 1-acid glycoprotein
• nonspecific binding
• pharmacokinetics
• drug-drug interaction
• therapeutic index

Article highlights

• PPB is widely applied in drug discovery and development to predict DDIs, estimate TIs, and develop PK/PD relationships.

• Many PPB methods have been developed and equilibrium dialysis method is most commonly used in the pharmaceutical industry.

• Several novel methods are available to measure PPB of highly bound compounds and they enable accurate measurement of f_u much below 0.01.

• PPB does not affect in vivo efficacy and SAR or structural modification to alter PPB is generally not recommended with some exceptions.

• PPB displacement interactions are rarely of clinical significance.

Acknowledgments

The author greatly appreciates the help of Sophia M. Shi in editing the manuscript.

Declaration of interest

L Di is an employee of Pfizer Inc. The author has 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.

Additional information

Funding

This manuscript was not funded.