1. 2017-06-14…15 NIAID PK-PD Workshop: A quick summary
What did we learn?
John H. Rex, MD
Please distribute freely
NIAID PK-PD - Summary ideas

2. What PK-PD can / cannot do
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
NIAID PK-PD - Summary ideas

3. 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)?
NIAID PK-PD - Summary ideas

4. Standardization might help But let’s avoid the illusion of skill…
Simple steps towards reduced variation in PD target measures
Step 1: Detailed reporting on methods (ARRIVE animal data guidelines)
Step 2: Using known ways to reduce variation (e.g., methods that reduce CFU/ml variation in the inoculum)
Step 3: Seek to compare across labs
It seems unlikely that we’d do a multi-lab (M23-like) study
But, could we begin to build a database of standard (QC?) isolates tested vs. standard benchmark compounds?
Is it useful to discuss how we do target attainment math?
Current: Worst case ounding limits (MIC90, 95% CI PK limits)
For the future: Variance-based (incorporate variance of observed PD targets, PK parameters, MIC ranges)
NIAID PK-PD - Summary ideas

5. 2017-06-15 - NIAID PK-PD - Summary ideas
Gaps / Transformation
We lack validated cIAI & cUTI models
Would routine use of real-time PK improve outcomes?
Is point-of-care PK possible?
How do we develop products without an MIC?
It’s not clear that PK-PD provide the orthogonal causality support
How do we develop combinations?
How do we do preclinical PK-PD?
How do we do the clinical testing for a combination regimen?
TB as a paradigm for both: a workshop is coming
Studies of specific clinical questions
Exploring CSF penetration (and its meaning)
More use of PBPK (Physiologically-based PK)
Do we have the (compartment-level, by-age) data we need?
NIAID PK-PD - Summary ideas

6. Possible outputs from this meeting
This workshop was an experiment. Thanks to NIAID for organizing and thanks to all of you for participating. What might we do / see next?
Summary of best practice as of today
Ex: We might write a summary paper (or two)
NB: Discussions at this workshop should not be taken as regulatory guidance!
Ideas gaps to address via funder-led work
Ex: NIAID might seek to fund work addressing the gaps
A further step in the conversation on this topic
Ex: We might carry on the debate via further workshop(s)
NIAID PK-PD - Summary ideas