Rethinking Pharmacokinetics With Les Benet, PhD

Les Benet, PhD, professor in the UCSF School of Pharmacy’s Department of Bioengineering and Therapeutic Sciences, is boldly rethinking how pharmacokinetics is taught and applied.  

Benet recently published a groundbreaking new tutorial, called “Simplifying Pharmacokinetics, Applying it to Drug and Dosage Form Development, and Making Drug Dosage Decisions in Clinical Medicine: The Adaptation of Kirchhoff’s Laws from Physics,” that offers an alternative to traditional models based on differential equations. Benet instead applies Kirchhoff’s Laws, long used to analyze electrical circuits, to simplify and improve how drug clearance and dosage decisions are calculated.  

 Benet, a pioneer in bridging laboratory research on pharmacokinetics with advances in clinical pharmacology, will start teaching the new methodology this fall in the graduate pharmacokinetics course and next spring as part of the school’s Pharmacokinetics for Pharmaceutical Scientists course.  

We spoke with Benet about what inspired this innovation, what it could mean for the next generation of pharmaceutical scientists, and why this work challenges nearly a century of pharmacokinetics teaching.  

Q: What inspired you to develop this simplified pharmacokinetics methodology, and how does it differ from traditional approaches involving differential equations?  

A: About 10 to 12 years ago, our lab began examining why our field often struggles to accurately predict how a new drug behaves in the body and how that relates to its efficacy and toxicity.  

All the published experimental data best fit a model I helped develop in 1973, the well-stirred model (WSM), which had long been considered physiologically unrealistic. That model was derived using differential equations, the standard method at the time.  

Then in 2022, I realized I could derive the same WSM equations by adapting Kirchhoff’s Laws from physics — without using differential equations. This was a significant breakthrough. With collaborators including [Department of Pharmaceutical Chemistry Professor Emeritus] Kenneth Dill, PhD, and graduate students Jonathan Patcher, PhD, and Jasleen Sodhi, PhD, we published a paper demonstrating that we could re-create these pharmacokinetic models without relying on physiologically questionable assumptions.  

Q: How does this new framework improve how clinical pharmacokinetics is taught and applied, particularly in drug dosing decisions?  

 A: Using Kirchhoff’s Laws, we can accurately sum entering and exiting drug clearances, the rate at which the body removes a drug from the plasma, at any site of measurement. This helps distinguish between processes that act in parallel — like hepatic and renal clearance — and those that are in series, such as gut absorption followed by hepatic metabolism.  

 This methodology allows us to build more robust and accurate models without relying on oversimplified assumptions. For example, we often assume that drug clearance from the absorption site doesn’t affect measured drug clearance after dosing, but that’s not always true.  

 These new equations make it easier to explain complex pharmacokinetic phenomena and to make better-informed dosing decisions.  

 Q: You’ll be teaching this material for the first time this fall. What are you most excited for your students to take away from the experience?  

A: We’re proposing a fundamental change to a field that has been taught the same way for nearly 100 years, so it's inherently controversial. That’s why I waited until we had published 10 peer-reviewed papers before introducing the concept into the classroom.  

 The first audience is graduate students preparing to become drug development scientists rather than clinicians. My goal is to equip them with tools that allow for new drug delivery strategies — ideas that weren’t possible under the historical models we’ve relied on. Ultimately, that benefits clinicians by helping them dose drugs in ways that enhance efficacy and reduce toxicity.  

 Q: What’s your vision for how this methodology might influence the future of pharmacokinetics education and research across academia and industry?  

Pharmacokinetics can be taught using a methodology that is much easier to understand and apply. The tutorial deemphasizes several traditional concepts that have little relevance to the fundamental goal of clinical pharmacokinetics: guiding drug dosing decisions.   

 Long term, we believe this could also spark a paradigm shift in drug development. For instance, separating drug concentrations related to efficacy from dosing amounts tied to toxicity could allow for more precise therapies. These ideas are still conceptual, but we’re starting to test them in vivo, and I believe the findings could transform both education and practice in pharmacokinetics.