NIAID workshop: What is a robust PK-PD package?

Dear All:

The ~150 of us who gathered in Washington yesterday and today for the NIAID’s PK-PD workshop enjoyed a very rich conversation. It’s really hard to capture the full debate, but here is a brief slide set and as well a written summary of the meeting that provide the main points. More materials can be found online at this link.

The heart of the workshop was an extended debate about the nature of a “robust PK-PD package.” We also had a good discussion of what PK-PD both can and can’t do. See the slides, but the critical material is also excerpted below my signature.

Given the intrinsic variability in all biological assays, a core message was that PD target estimates may differ substantially by method and by lab.  A lot of the discussion focused on  ways to manage this variability. Building substantial depth by testing multiple isolates in multiple models and by use of benchmark (internal control) compounds were all discussed as ways to build confidence around an estimate.

Overall, I see PK-PD as a field that continues to evolve rapidly. You definitely need an expert at your side (and it was great to have all the PK-PD gurus in the room!) but it is possible to find solid ground via careful work.

Many thanks to team NIAID for making this event happen with a special thanks to Tina Guina and Ann Eakin for their proactive leadership!

All best wishes and safe travels, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Chief Strategy Officer, CARB-X | Expert-in-Residence, Wellcome Trust
Follow me on Twitter: @JohnRex_NewAbx

Text from two of the slides

What is robust dose selection?

  • “Robust” should reduce risk. What reduces risk?
    • Standards:
      • Use benchmark compounds as internal controls. We do this implicitly within classes – being explicit about this is helpful
      • Isolates: Consider the use of standard (QC-like) PD isolates
    • Orthogonal data:
      • Test a range of isolates & models.
      • Chose them to explore relevant variation
    • Buffer your P3 study vs. patient-level PK variation
      • Select dose to give maximum exposure within tox limits
      • When all you have is HV data, anticipate greater variance in patients
      • Get PK in suitably diverse patient settings as early as possible
    • Exposure at the site matters: Keep site PK in mind … is plasma a good correlate or do you need to go deeper (e.g., ELF)?

What PK-PD can / cannot do

  • Can
    • Early: Derisk dose-selection
    • Mid: Enable programs to happen at all in settings where clinical data are limited
    • Late: Help with labeling questions about dosing and PK in special pops, pediatrics, drug-drug interactions, etc.
    • Late: Provide support to breakpoint determination
  • Cannot (necessarily)
    • Speed the program: PK-PD is often iterative
    • Make overall program smaller: You may well need to spend time exploring / confirming PK in relevant patient settings

Share

Impact of PASTEUR: 9.9m lives saved, ROI of 125:1

Impact of PASTEUR: 9.9m lives saved, ROI of 125:1 Dear All (and with thanks to Kevin Outterson for being lead author on this newsletter), (wonkish alert on this one … refresh your coffee and dig in!) The Center for Global Development have released a blog post and a paper estimating the potential impact of the PASTEUR Act.

Five FDA RFPs! Antifungal animal models, MIC breakpoints, and more!

Dear All, I just today learned that FDA have posted their FY 2023 funding opportunities. All the details are on this webpage and I’m just going to reproduce the text below my signature for your reference. I’ll also add a few details in italics. Lots of good opportunities here! –jr John H. Rex, MD |

WAAW! Must-Read Article, A Quiz, A Video, A Call to Action

Notes: Newsflash … BARDA have opened their long-running BAA-18-100-SOL-00003 to include support for antifungal agents. Search for “antifungal” in the posted .pdf to find the text. The first deadline for proposals is 15 Dec 2022 and further deadlines will doubtless follow: as shown on page 9, this BAA has offered 4 deadlines/year since 2018!  Dear All, In

Fireside Chat with AMR Action Fund CIO Martin Heidecker

Dear All, Ahead of World Antimicrobial Awareness Week, I sat down with AMR Action Fund Chief Investment Officer Martin Heidecker for a Fireside Chat. It was a fabulous conversation that covered everything from how the Fund’s investment process works to what it’s looking for in portfolio companies to broader investment trends in the AMR space.  As

Scroll to Top