Tweetorial: Pharmacokinetics and Publications

15 July 2021

This was the first tweetorial I published on Twitter that got the whole tweetorial ball rolling. A couple of things came together to convince me this was worth some effort:

• I was on vacation that week and it was a slow posting week. I really do try to unplug from the office while I’m away, and that means taking a pause on reading literature.

• I had read some truly awful publications lately where people were drawing some horrible in vivo conclusions not warranted by the data, largely because they had not properly characterized their compounds’ PK.

• I thought, “Hey, this is something I know something about! I can be useful here.”

• Industrial chemists are underrepresented on Twitter. It’s a preferred medium for academics, and I felt like it was about time to start owning the part of the conversation where we have some expertise.

Thus began the tweetorial series. Engagement on these posts has been really superb, so it seems there’s indeed an appetite for people who want to know more about this stuff. It hasn’t been hard to come up with new topics subsequent to this one. There are so many things that are interconnected that once the ball started rolling, it kept on rolling.

I also have no idea where I got the idea to add a GIF to most of the posts. I started out looking for a cute mouse to grab attention on the first post. Then it just kind of became fun to keep adding more. I don’t always know all of the cultural references - I just try to find things that fit with the theme I’m speaking to.

Keith Hornberger @KRHornberger

🧵PSA: we need to chat about pharmacokinetics & pubs. If you plan to publish in vivo PD/efficacy studies, the minimum credible accompanying PK package is an IV leg + an IP/PO leg if that's your eventual route. In the same species, preferably at the planned efficacy dose. 1/

Keith Hornberger @KRHornberger

The minimum IV parameters are: Cl, Vss, AUC_0-last/inf. Minimum PO/IP parameters are: Cmax, tmax, AUC_0-last/inf, and F. All of this info is needed to properly frame the pharmacokinetic behavior of the compound. Actually showing the PK plots is even better. 2/

Keith Hornberger @KRHornberger

As supporting ADME, plasma protein binding in the same species is essential. Please draw IC50 lines across a PK graph only with free drug-corrected plasma concentrations. Doing otherwise indicates a lack of understanding of the free drug hypothesis and is just plain invalid. 3/

Keith Hornberger @KRHornberger

This stuff really isn't optional. Without it, at best, you're looking through a glass darkly. At worst, you could be publishing hot garbage based on a presumed mechanism of action that's totally incorrect. PK, PD, and efficacy should fit together to tell a sensible story. 4/

Keith Hornberger @KRHornberger

Don't look at this as a burden. Look at it as an opportunity to fully understand your compound(s). If e.g. your PK exposure gives free drug levels below the target IC50 for the entire dosing interval and efficacy is still amazeballs - maybe wonder if that's on-mechanism. 5/

Keith Hornberger @KRHornberger

The proliferation of PD/efficacy studies with inadequate accompanying PK studies, even in med chem journals, is staggering. These are clear revision flags during peer review. That so much slides through suggests most reviewers are also unaware of these things. 6/

Keith Hornberger @KRHornberger

We can do better. First, folks are often surprised to learn that basic rodent PK studies can be run at contract labs around the world for a few thousand $. Given the time, effort, and $ that went into all the rest of the work, this is money well-spent. 7/

Keith Hornberger @KRHornberger

Second, I'd love to see academic institutions open up broad MSAs with contract labs and then give all their researchers access for requesting PK studies. Maybe this already happens at some places. Share your success stories. Volume business = reduced costs. 8/

Keith Hornberger @KRHornberger

Lastly, most importantly, be PK aware. Learn some basic pharmacokinetics - tons of online resources for this. Know why these studies need to be present in your own work, and expect it from others. Result: higher quality published work we can all take to the bank. /end

Keith Hornberger @KRHornberger

PS - there's a discussion to be had about some of the finer details above. But I hope the broad strokes can garner some agreement. Let's work together to make the enterprise more integrated and interdisciplinary. Love, your friendly neighborhood medicinal chemist. ❤️