Thread by @KRHornberger

I support our group with early human dose prediction. Not the fancy, need-tons-of-software and a DMPK pro kind. Just the kind that uses some basic algebra. HDP is a unifying concept for med chemists. It’s the master optimization parameter, and it can’t be easily cheated. 1/

Here’s a wonderful paper from AstraZeneca that speaks to this conceptual framework - this isn’t something I invented. The concept has been around for years. Required reading! 2/
pubs.acs.org/doi/10.1021/mp…

And another. 3/
pubs.acs.org/doi/10.1021/ac…

At my own shop, I’ve built a suite of tools 🛠 in Excel to assist with allometric scaling of Cl/Vss and modeling common HDP scenarios. Playing with input parameters in real time in these sheets is a great way to grasp how they impact dose. 4/

Beyond the beginnings you can get from Excel, for projects that are in full-on lead optimization, I’ve also built workflows in @knime that can automate this process for many compounds at once. 5/

None of this replaces expert input from your friendly neighborhood DMPK person. But I’m repeatedly astonished how close to the final mark you can get with basic modeling. Medicinal chemists need to claim and own and normalize routine basic HDP. 6/

The biggest barrier is, I think, fear of the math. But you only need some basic algebra to manipulate the equations (and a smidge of calculus if you want to do the derivations). Plus some time invested by one person in a group in learning Excel functions and KNIME pipelining. 7/

Big shoutout to my ex-BI colleague Rob Hughes (also ex-Pfizer) who was WAY ahead of most of us on this stuff. He more than anyone showed me the way and had a huge impact on my own thinking. 8/

Lastly, yes, this is me reclaiming some math after yesterday’s depressing realization that I no longer know quantum chemistry. I make no apologies for boosting my own confidence. 😂 /end