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