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 imaging	Low energy (3H or 14C) radio-labeled analyte with Whole-Body AutoradiographyMALDI-MSILaser-capture microdissection
Single* site	Aptamers on a probeMicrodialysis	Grind 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

• the 14-15 June 2017 NIAID PK-PD workshop,
• the excellent EMA guideline on PK-PD for antibacterials, and
• the discussions of PK-PD at the 1 Mar 2017 FDA workshop on animal models in support of narrow-spectrum agents for A. baumannii and P. aeruginosa.

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:

• 5-8 Sep 2017: ASM-ESCMID conference on antibiotic R&D, including the CARB-X + GARDP Antibiotic Bootcamp
• 13 Sep 2017 (DC): FDA-CDRH workshop on diagnostic devices for detecting antimicrobial susceptibility & resistance
• 4-8 Oct 2017 (San Diego): IDWeek
• 29 Oct-1 Nov 2017 (Santa Fe): Keystone Symposium – Antimicrobials and Resistance: Opportunities and Challenges
• [NEW] 11-19 Nov 2017 (Annecy, France): International Course on Antibiotics and Resistance (ICARE)
• 24-27 Nov 2017 (Taipei): 30th International Congress of Chemotherapy & Infection (ICC)
• 12-14 Feb 2018 (Baltimore): ASM Biothreats Conference
• 11-16 Mar 2018 (Ventura Beach): Gordon Research Conference on Antibacterial Discovery
• 21-24 Apr 2018 (Madrid): ECCMID
• 7-11 Jun 2018 (Atlanta): ASM Microbe
• 22-27 Jul 2018 (Bryant University, Smithfield, RI): Gordon Research Conference on Drug Resistance for Cancer, Infectious Disease and Agriculture