PK measures in space and time: Summary of high-resolution methods

Dear All: 

I recently sent around discussions of ways to measure/estimate drug concentrations both in living animals (aptamer-based probes, Kevin Plaxco’s group) and with sufficient spatial resolution to permit construction of 2d/3d drug concentration maps (MALDI-MSI, David Perlin’s group).

In the context of our efforts to learn to better apply PK-PD (e.g., the 14-15 June 2017 NIAID PK-PD workshop), these notes generated a lot of interest and in particular Ed Weinstein (FDA) made me aware of a book chapter in which he and his co-authors had looked at a range of such techniques.

Finding this intriguing, I worked with Kevin, David, and Ed to prepare a summary of the range of current techniques for doing something that you could loosely call PK in high resolution by time and/or space. Several ways of categorizing the methods are shown in the table below and you’ll find more details on each in this downloadable summary document. It’s fascinating to see them side-by-side and realize the wealth of opportunities that exist.

Each approach has strengths and weaknesses but I must say that MALDI-MSI and aptamer-based probes really standout as exciting new tools by offering strong spatial information (MALDI-MSI) or easily obtained continuous drug measures (aptamer-based probes) based in both cases on measurements of the unmodified analyte

Overview of techniques: Specialized probe and/or modified analyte vs. general approach to detection of unmodified analytes

Continuous, with
potential for in vivo
Single* time point
Offers
spatial
resolution
Fluorescent probeHyperpolarized NMR/MRIPET ImagingPhotoacoustic imagingLow energy (3H or 14C) radio-labeled analyte
with Whole-Body AutoradiographyMALDI-MSILaser-capture microdissection
Single*
site
Aptamers on a probeMicrodialysisGrind tissue & assay extract

*Of course, any single time point or single site method could be extended by doing serial sampling but there are practical limits to how much of this you can do.

Rough rank order of spatial imaging resolution methods:

  1. Higher resolution: MALDI-MSI, autoradiography
  2. Lower resolution: Fluorescent probe, Hyperpolarized NMR/MRI, PET Imaging, Photoacoustic imaging, Laser-capture microdissection

Absolute analyte concentration data: (1) Aptamers on a probe, (2) Microdialysis (with difficulty), (3) Laser-capture microdissection, and (4) Grind tissue & assay extract

If this intrigues, you may also want to look both at this book and PK-specific chapter within it:

  1. Book: Imaging Infections : From Bench to Bedside. S. K. Jain.: https://link.springer.com/book/10.1007%2F978-3-319-54592-9
  2. Chapter in said book Ordonez, A. A., L. E. Bambarger, S. K. Jain and E. A. Weinstein (2017). Biodistribution and Pharmacokinetics of Antimicrobials. Imaging Infections : From Bench to Bedside. S. K. Jain. Cham, Springer International Publishing: 209-222. :https://link.springer.com/chapter/10.1007/978-3-319-54592-9_10

And to round out this summary of PK-related ideas, you might also want to review the material from

MANY thanks to Ed, David, and Kevin for provoking this interesting exploration!

All best wishes, –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. See past newsletters and subscribe for the future: https://13.43.35.2/blog.html

Upcoming meetings of interest to the AMR community:

Share

ENABLE-2 funding now includes Hit Identification & Validation

Dear All, I wrote on 25 Aug 2023 about the ENABLE-2 program and its support for hit-to-lead compound development. As a reminder, that program is focused on molecules with the potential to be direct-acting therapies for one or more of the following priority pathogens: ESBL-producing/carbapenem-resistant Enterobacteriaceae (E. coli, K. pneumoniae), P. aeruginosa, A. baumannii, methicillin-resistant S. aureus, or vancomycin-resistant E. faecium. Adding to that program, there is now an ENABLE-2

NIAID/DMID thinking for FY2026: Antibacterials, Phage, and Antifungals

Dear All, NIAID’s DMID (Division of Microbiology and Infectious Diseases) recently held a council meeting during which they proposed program concepts that encompassed both antibacterial therapies (including phage) as well as antifungal therapies for funding in FY 2026 (the year that would run from 1 Oct 2025 to 30 Sep 2026). There is no guarantee that

WHO Antibacterial Pipeline Review: Update thru 31 Dec 2023

Dear All, WHO have released an update through 31 Dec 2023 of their ongoing series of antibacterial pipeline reviews! Here are the links you need: The report: 2023 Antibacterial agents in clinical and preclinical development: an overview and analysis and a press release about the report. Infographics: Key facts and recommendations from the 2023 antibacterial agents in clinical

The (confusing!) language of AMR: ChatGPT tries to help!

Dear All (Wonkish alert! Not technical but lengthy … so settle in and enjoy the ride!): Regular readers will know of my fascination with language: e.g., this 20 Feb 2020 newsletter entitled “Language Matters: CRE vs. CPE; SDD vs. I; And MDR, XDR, PDR, UDR vs. DTR.” How about that for acronymics taken to Olympian

Scroll to Top