Back to the Top
The following message was posted to: PharmPK
Dear list,
I wonder if anyone on this mailing list has got some insight on MR
spectroscopy's possible application in drug PK/PD study? A google
site search on boomer.org's PK/PD mail archive yielded only few
out-dated hits, and I seem to be only aware of PET's potential on
PK/PD trial, really appreciate it if someone would point to me some
review articles.
Best regards,
Yours sincerely
Zhang Hao M.D.
Senior Pharmacological Physician
Clinical Pharmacology, Global Clinical Development
UCB Pharma R&D
Chemin du Foriest
Braine-l'Alleud
B-1420 Belgium
Tel: +32-2-386 6035
Fax: +32-2-386 3537
Back to the Top
The following message was posted to: PharmPK
Dear Dr. Hao:
I am delighted to answer your question about "insight on MR spectroscopy's
possible application in drug PK/PD study", inasmuch as this is precisely
the focus of the USC Pharmacokinetic program.
Years ago we started using radiolabeled drugs to begin studying,
non-invasively, the biodistribution and the target pharmacokinetics of
those drugs. We started with 5-Fluorouracil, which could be radiolabeled
intrinsically with 18F, and with cisplatin and carboplatin, which we
radiolabeled with 195mPt. Such work, started at USC, has now been continued
at many other places. Using this technology we were the first to show that
there was a direct association between the uptake of radioactivity
following administration of 18F-5-FU and response to chemotherapy. These
studies were done in animal tumor models and in humans, and both our work
and that of a number of other laboratories have been published. There are
still a few investigators who are continuing studies with 18F-5FU for tumor
PK. References to some of those early studies can be found in a review
article we published in 2000: 19F-MRS Studies of Fluorinated Drugs in
Humans. Walter Wolf, Cary A. Presant and Victor Waluch. Advanced Drug
Delivery Reviews, 41, 55-74, 2000. This review article also summarizes the
19F-MRS work to that date.
Yet while radiolabeled drugs can be detected with a very high sensitivity,
they do not provide any chemical information. 18F-measurements following
administration of 18F-5FU provide a sum of the parent compound as well as
of all its anabolites and catabolites. We therefore switched to the use of
in-vivo NMR (now called MRI and MRS), as soon as this technique became
available, and published, in 1990, the first human study using 19F-MRS of
5-Fluorouracil (Proc. Natl. Acad. Sci., 87, 492-496, 1990), following the
work of John Griffiths et al. who had performed the first 19F-MRS animal
studies (Br. J. Cancer 50, 113-7, 1984).
The most significant outcome of our human PK studies has been to show that
"trapping" of 5-FU is a necessary, yet in itself not a sufficient condition
for response to chemotherapy with 5-FU. Patients who do not trap 5-FU
(trapping being defined as an intratumoral elimination half-life of 5-FU of
20 minutes or greater) will not respond. Of the 50 patients we had studied
following administration of 5-FU as a bolus, 29 were trappers and 17 of
these were responders. 31 were non-trappers and NONE of them responded.
These results have since been confirmed in a number of other laboratories.
One of our most recent publications is a SWOG sponsored study
(Investigational New Drugs 20, 369-376, 2002). The p-value of the
association between trapping and response to 5-FU bolus is <.00001.
While we are continuing focused on studies with 19F-MRS for some of the
reasons listed below, other laboratories have ongoing PK studies using 1H
and 13C. The main advantages of 19F-MRS studies are:
1. There are no naturally occurring fluorinated compounds in the body.
Thus, we do not have to fight background signals, which in the case of 1H
or 13C can be overwhelming.
2. The chemical shift range of 19F is ~ 200 ppm, as opposed to ~12 ppm for
1H. Thus, resolution of individual peaks, normally broadened in vivo, is
much better than with 1H.
3. The number of drugs that are fluorinated is increasing steadily. Thus,
19F MRS measurements meet a very definitive need in both drug development
and drug utilization.
4. The NMR sensitivity of 19F is very high, 84% that of 1H.
Finally, let me add a few comments on noninvasive PD measurements. We have
been improving the DCE-MRI method, which, in our hand, is allowing us to
measure the pharmacodynamic effect of anti-angiogenic agents. In a limited
study of patients treated with docetaxel we have obtained a statistically
significant association between response, time-to-progression and survival
to docetaxel and a >25% decrease in tumoral perfusion. (Abstract 5343,
Proceedings of the AACR, 44:, 2nd. Ed, 2003). But that is a whole field in
itself.
Yes, noninvasive methods are rapidly becoming very important in both drug
development and in drug studies aimed at drug optimization and
individualization. MRS and MRI methods have unique advantages and
limitations, as do all other noninvasive imaging techniques. The need to
correlate these various noninvasive technologies using a systems approach
is one of the, if not THE main goal of the USC Pharmacokinetic Imaging Program.
I hope I have addressed some of your questions, and feel free to contact me
for additional references to our work and that of others, as well as to any
other questions you may have.
--
Professor Walter Wolf, Ph.D. President, Correlative Imaging Council,
Society of Nuclear Medicine
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
University of Southern California 1985 Zonal Ave., Los Angeles, CA 90089-9121
E-Mail: wwolfw.at.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
Back to the Top
The following message was posted to: PharmPK
Dear Prof. Walter Wolf,
Thank you so much for the quick response and detailed review of the
MRS PK work. I have some background of fMRI on animal (tumor
antiangiogenesis) and BOLD human brain mapping, but I don't know much
about MRS, your reply indeed sheds light on this area for my knowledge
base. I'd further the discussion off the list later.
Clinical MRI scanner is widely available in most medical center
nowadays, therefore it should be more convenient than before to
explore the field of non-invasive clinical pharmacology using
fMRI/MRS, in sense of new compound phase I clinical trial.
Best regards,
Yours sincerely
Zhang Hao
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)