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Dear All:
Does anyone can tell me or provide me some useful paper about how to interpret a certain value of volume of distribution when we get it from mouse, rat or dog, monkey preclinical PK studies? Just like we can differentiate the drug with plasma clearance as low, medium or high hepatic extracted drug when the values located in the range of <30%HBF, 30~70%HBF and >70%HBF, respectively. But I don't know very clearly about the breakpoint values for volume of distribution. Is it similar or different in different species? This question has puzzled me for a long time and it's hard to find a useful paper to help me. Thanks!
Jian
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Dear Jian,
useful starting point for interspecies volume of distribution concerns could
be the evidence that, for many conventional drugs, Volume of Distribution
(Vd) can be scaled allometrically by applying the exponent 1.00, i.e. by
considering a direct relationship between Vd and Body Weight (BW), i.e.
ratio Vd/BW = constant.
Kind Regards
Stefano
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Dear Stefano,
I do not wish to restart a topic that has made it's appearance on this listserv more times than I can count (I have only been a member since the early '90s), but I must restate, expecting many to weigh in, that Vd/BW is not a constant. While there may be a relationship between certain species (ie. rat, dog, human), for many drugs, this relationship is not appear to be appropriate outside of this narrow number of species. Allometry is a useful tool to help with first dose in human selection, but it is of VERY VERY limited value in other species.
R.P. Hunter (2010) Interspecies allometric scaling. In Handbook of Experimental Pharmacology: Comparative and Veterinary Pharmacology, vol. 199; Eds: F. Cunningham, J. Elliott, & P. Lees; Springer Verlag. pp. 139-157. R.P. Hunter & R. Isaza (2008) Concepts and issues with interspecies scaling in zoological medicine. J. Zoo Wild. Med., 39, 517-526. R.P. Hunter, I. Mahmood, & M.N. Martinez (2008) Prediction of xenobiotic clearance in avian species using mammalian or avian data: How accurate is the prediction? J. vet. Pharmacol. Therap., 31, 281-284. M. Martinez, I. Mahmood, & R.P. Hunter (2006) Interspecies allometric scaling: prediction of clearance in large animal species: Part II: mathematical considerations. J. vet. Pharmacol. Therap., 29, 425-432. I. Mahmood, M. Martinez, & R.P. Hunter (2006) Interspecies allometric scaling. Part I: prediction of clearance in large animals. J. vet. Pharmacol. Therap., 29, 415-423.
Rob Hunter, M.S. Ph.D.
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Although I havent seen it in literature, can you do the classification based on total body water content? Volume of distribution unlike clearance parameter, is difficult to use to drive SAR development in discovery.
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The following message was posted to: PharmPK
Dear Satya Jadhav,
You said:
"Although I haven't seen it in literature, can you do the classification
based on total body water content? Volume of distribution unlike clearance
parameter, is difficult to use to drive SAR development in discovery."
Actually, it's quite the opposite. It's possible to develop a useful SAR
(QSPR) for volume of distribution, but not for clearance in genl. We have a
QSPR for volume of distribution in ADMET Predictor(TM) with an RMSE of 0.35
log units and MAE of 0.26 log units. QSPRs for clearance can be developed
for certain specific clearance pathways, but a general clearance model
defies modeling at this point in time. Volume of distribution (per kg) is
also generally much more consistent across species than clearance.
Expression levels of enzymes and transporters (when they are generally the
same enzymes and transporters) vary considerably among species, confounding
the problem.
Rather than animal data, PBPK modeling provides the best estimate of human
volume of distribution in many cases. Calculation of tissue:plasma partition
coefficients (Kp) provides reasonably good estimates of tissue distribution.
In our experience, experimental Kps from rat can also be used directly for
prediction of distribution in human with reasonable accuracy for many
(most?) drugs.
GastroPlus(TM), SimCYP(TM), and PK-Sim(TM) are used routinely for such
analysis.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Dear Rob and all:
What do people do now to determine the first dose to be given in
man? Is there any generally agreed-upon protocol?
And after that, is there an agreed-upon protocol for determining how
to explore the dose-respponse relationship?
Very best regards,
Roger Jelliffe
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Dear All:
Many thanks for your quick response on my question. But maybe I don't explain very clearly, what I want to know is how to judge a certain value of Vz or Vss we got from preclinical or clinical PK study? For example, if the Vz=1.5 L/kg, does it mean it is a low volume of distribution, which indicate that the drug has a limited extravascular distribution? What's the breakpoint to differentiate a certain drug as a low, medium or high volume of distribution? Are there any differences among mouse, rat, dog, monkey and human for the breakpoint values?
Jian
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Jian,
> What's the breakpoint to differentiate a certain drug as a low, medium or high volume of distribution? Are there any differences among mouse, rat, dog, monkey and human for the breakpoint values?
Pharmacokinetic science is much simpler than you are trying to make it. Volume of distribution is a continuous value parameter therefore there are no breakpoints. So you have nothing to worry about :-)
In addition, Vz is a bad way to describe volume of distribution. See Gobburu & Holford 2001. So you have only have to think about one volume instead of two :-)
Nick
Gobburu JV, Holford NH. Vz, the terminal phase volume: time for its terminal phase? J Biopharm Stat. 2001;11(4):373-5.
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The following message was posted to: PharmPK
Roger,
You asked:
" What do people do now to determine the first dose to be given in
man? Is there any generally agreed-upon protocol?"
Pfizer uses GastroPlus PBPK models exclusively for all FIH predictions
according to a presentation by Natalie Hosea at AAPS last year.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Hi Forum
Roger asks if there is any agreed-on protocol for determining the first dose to be given to man. I hope we never get to such a thing because each medicinal molecule should be considered separately. There is a world of a difference between yet another ACE inhibitor for example and a Tegenero-type immune response modifyer or a novel antibody. I think we are already too close to having a box-ticking mentality that fails to recognise this because it takes a bit too much comfort from having followed general precedents and guidelines that may be very helpful but cannot be expected to apply to truly novel products.
Andrew Sutton
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Hi all,
I agree with Nick's comments that the volume of distribution is a "continuous" parameter. Theoretically, that is.
On the practical side, though, wearing the medicinal chemist's hat, we tend to "bin" this property. We often see that depending on the functional groups present in the drug's structure, the volume of distribution is either low (below 1L/kg), moderate (between 1 and 5-8L/kg) or high (greater than 8L/kg).
I also agree with Walt's earlier comments on predicting volume of distribution and clearance. Actually, it is remarkable how well the volume of distribution (specifically in rat, where most of my experience is) can be engineered into a structure once you have the experimental data for a few analogs.
On the other side, prediction of in vivo hepatic clearance from in vitro intrinsic clearance with microsomes has a much poorer record, IMHO. Too poor to actually be useful in early new drug research, when most compounds are unoptimized and very little specific information is known about their biotransformation..
Cheers,
Dario
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Dear Jian,
Dont know about a specific paper, but you should get some idea by reflecting on what Vdss represents: Physiology and the physicochemical properties of the drug. And as the name suggests it tells you something about the distribution.
So, some pointers are (for an adult human):
A human a Vdss (plasma) of about 3 L suggests that the drug does not leave the circulation (eg antibodies have low Vdss 5-7 L).
Smaller than 3L usually suggest you have a problem. I would check the calculations first. I cannot think of a biology that supports such a number of the top of my head.
Total Body water is about 40 L. So a Vdss close to that suggests that the drug stays in the body water (not a proof though).
Larger than this suggests wider distribution, with very large number indicating accumulation in fat or sequestration etc.
For other species, do the same: look at their respective volumes.
Bart
Bart Laurijssens
BEL Pharm Consulting
Moulin d'Ozil, Chambonas 07140, France
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The following message was posted to: PharmPK
In general -
Vd = 0.05 - 0.25 L/kg / distribution in plasma / or extracellular fluids / extent is VERY LOW
Vd = 0.25 - 0.65 L/kg / intracellular water upto body water / extent is LOW
Vd = 0.65 - 5.0 L/kg / in total body fluids / extent is MODERATE
Vd = >5 / L/kg / distribution in deep tissues, peripheral tissues / extent is HIGH
Vd is dependent upon: 1) blood flow. 2) physiochemical properties of the drug. 3) Protein binding.
Units are L/kg (per kg enables cross species comparison).
Regards,
Anila
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Volumes of distribution are virtual numbers as the strong assumption is a same concentration in that volume.
In the real physiology that is not true (may be for the drugs only distributed in the vascular system). The example of the digitalin (>500liters) does not mean that it is distributed to the tip of your toes but rather due to its affinity to receptors. the end point is still to define the dose that shows efficacy/no toxicity.
Dominique Paccaly, PharmD
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The following message was posted to: PharmPK
Dear Dominique and all:
Thanks for your note about digitalin. The digitalis compounds have a
high tissue uptake which is responsible for their quite large apparent
volume of distribution. It is interesting also that the clinical effect of
digoxin, for example, and probably digitoxin as well, correlates very well
with the computed concentrations in the unobservable peripheral compartment
of a model having an absorptive, a central (serum) compartment, and a
peripheral nonserum compartment. The cardiologists seem not to have picked
up on this, although the data was well described in 1973. If you use
software to fit such a model to a patient's serum data, you will see the
close relationship between the peripheral compartment concentrations and
clinical effect, especially in acutely changing situations like the
conversion of atrial fibrillation to sinus rhythm, which everybody strongly
believes does not happen because they read the very underpowered studies of
Falk, et al, for example, How can you find a significant difference between
2 arms in there are only 12 patients in each arm? And how can you
extrapolate from a fixed protocol dosage (where neither body weight nor
renal function were mentioned in the data? You might look at:
Reuning R, Sams R, and Notari R: Role of Pharmacokinetics in Drug Dosage
Adjustment. 1. Pharmacologic Effects, Kinetics, and Apparent Volume of
Distribution of Digoxin. J. Clin. Pharmacol. 13: 127-141, 1973.
This relationship and model is what we have put into our clinical
software. It really works well. You might look at:
Jelliffe RW, Schumitzky A, Van Guilder M, Liu M, Hu L, Maire P, Gomis P,
Barbaut X, and Tahani B: Individualizing Drug Dosage Regimens: Roles of
Population Pharmacokinetic and Dynamic Models, Bayesian Fitting, and
Adaptive Control. Therapeutic Drug Monitoring, 15: 380-393, 1993.
We have had several patients who converted from AF to RSR with this
approach. Obviously not a randomized trial, but better than Falk et al....
we have had 3 of 4 convert using this approach.
Very best regards,
Roger Jelliffe
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Dear Andrew:
I am trying to optimize the process. Because of this, I am
interested in what people have done to date to arrive at this most important
first step. If one has a nominal reference policy, then it is often
possible, using methods similar to the stochastic dynamic programming
equations of Bellman, to improve on this. That is why I asked.
Yes. Of course each medicinal product has to be considered
separately. What I am trying to do is to find out the best overall process,
considering each compound as an individual entity - how best to learn what
its individual properties are, and as soon as possible, from a minimal
number of animals, and how best to use the information about these
individual compounds to develop the type of strategy I outlined.
I would be most interested in how people have done this
determination of the first dose in man, so that as a nominal individualized
policy for each individual drug, it might be improved upon.
Very best regards,
Roger Jelliffe
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Hi Anila
You have given some values for classifying the volume of distribution as low, moderate and high. My doubt is when we are doing pharmacokinetic study in preclinical species, how you will differentiate that the drug is distributed in extracellular fluid or intracellular fluid ? Do you have any reference to support these values ?
regards
Amol A Raje
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Dear Roger,
Majority of the times, we have used the NOAEL data of the most sensitive toxicity species to predict the FIM dose.
In order to predict human clearance, we have also tried other approaches like Allometric scaling (rule of exponents) and use of in vitro clearance (microsomes or hepatocytes) and in vivo clearance (preclinical species).
To further refine above approaches the correction for protein binding has also been tried.
Thanks
Tausif Ahmed, Ph.D.
Associate Director, DMPK and Toxicology,
Sai Advantium Pharma Ltd., Building 1, Plot No. 2, Chrysalis Enclave, International Biotech Park,
Phase II, Hinjewadi, Pune - 411 057,
Maharashtra, India
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The debate on volume of distribution starts with its definition which is Apparent volume of distribution.
see: http://aquaticpath.umd.edu/appliedtox/mod2-volumedist.html
"Having dropped apparent" is confusing for pharmacologists who try to associate it to a physiologic volume. Idem for the concentration in the apparent peripheral volume of distribution. What does that mean? This is only with the isolate heart experiment that we can access to effective/toxic concentrations. And this is what pharmacologists and toxicologists want to know is the maximum dose in the vascular system. With such a drug with a very high tissue/ blood/tissue partition coefficient a minor change in blood concentration is translated in high tissue levels. Considering that the size of heart (~2L) and the size of the apparent volume of distribution (~300L) I am wondering what does the correlation between apparent peripheral compartment concentration and digoxin effect means especially with a drug with such a narrow therapeutic index based on plasma concentration.
Dominique Paccaly.
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Following is the reference for the Vd value posted previously.
Physiological parameter values for physiologically based pharmacokinetic models.
Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Toxicol ind health, July 13, 1997, 4 (407-84)
Regards,
Anila
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Dominique,
> "Having dropped apparent" is confusing for pharmacologists who try to associate it to a physiologic volume. Idem for the concentration in the apparent peripheral volume of distribution. What does that mean? This is only with the isolate heart experiment that we can access to effective/toxic concentrations. And this is what pharmacologists and toxicologists want to know is the maximum dose in the vascular system. You might try reading this for an introduction to volume of distribution. There is more to it than the octanol:water partition coefficient taught to nursing students (http://aquaticpath.umd.edu/appliedtox/mod2-volumedist.html):
http://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/volume_of_d istribution_ppt.pdf
Real pharmacologists (and even toxicologists) should be concerned with concentrations in tissues not doses!
The concentration of drug in an isolated heart organ bath is no different from the concentration in plasma. At steady state the unbound concentration in the whole body or in an organ bath will be in the same as that at the site of action if there are no active transport processes in the way. It takes time for both plasma and organ bath fluid concentration to equilibrate with tissue sites of action. Neither are instantaneous. Indeed digoxin onset of effects in vitro are so slow that most organ bath experiments use ouabain which binds more rapidly and has a quicker onset of action (e.g. Naebauer et al. 1988). The same publication has an illustrative example showing digoxin effects taking about half an hour to approach a maximum effect. Have you ever thought about why it takes so long?
Early attempts to describe the delay in digoxin effects on the heart in relation to plasma concentrations used empirical compartmental models (Kramer et al. 1979) but more more physiological and mechanistic explanations for the delay in digoxin effects has been reported (Weiss et al. 2004).
What on earth makes you make a remark like this?
> With such a drug with a very high tissue/ blood/tissue partition coefficient a minor change in blood concentration is translated in high tissue levels
As far as I know a minor change in blood concentration will lead to a minor change in tissue concentration.
> Considering that the size of heart (~2L) and the size of the apparent volume of distribution (~300L) I am wondering what does the correlation between apparent peripheral compartment concentration and digoxin effect means especially with a drug with such a narrow therapeutic index based on plasma concentration
The empirical correlation between the time course of apparent peripheral compartment concentration and the time course of digoxin effect means that it takes time for digoxin to produce its effects. You cannot ignore time. A 1 mg bolus dose of digoxin will produce a peak plasma concentrations close to 50 ng/mL (25 times bigger than the usual target concentration) (Kramer et al. 1979). This concentration would certainly cause death if it remained that high. But because if falls quickly these concentrations are well tolerated in humans. An interesting paradox that sometimes confuses naive cardiologists is that while the concentrations are falling the effects are increasing which means there is a negative correlation between concentration and effect. This can be understood if you don't ignore time.
Nick
NAeBauer M, BOeHm M, Brown L, Diet F, Eichhorn M, Kemkes B, et al. Positive inotropic effects in isolated ventricular myocardium from non-failing and terminally failing human hearts. Eur J Clin Invest. 1988;18(6):600-6.
Kramer WG, Kolibash AJ, Lewis RP, Bathala MS, Visconti JA, Reuning RH. Pharmacokinetics of digoxin: relationship between response intensity and predicted compartmental drug levels in man. 207-46. 1979;7(1):47-61.
Weiss M, Kang W. Inotropic effect of digoxin in humans: mechanistic pharmacokinetic/pharmacodynamic model based on slow receptor binding. Pharm Res. 2004;21(2):231-6.
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The following message was posted to: PharmPK
Nick:
In today's reply to Dominique you make a very important point:
>Real pharmacologists (and even toxicologists) should be concerned with >concentrations in tissues not doses!
I should make a slight change to that statement:
>Real pharmacologists (and even toxicologists) should be concerned with
>the rate of change (kinetics) of concentrations in tissues not doses!
And let me point out again, as this group has heard me stress before, that noninvasive measurements are probably the only manner in which we can measure the rate of change (kinetics) of concentrations in human tissues in vivo. And that methods and instruments for such measurements - PET, MRI, MRS, Optical - are available today.
We should not limit ourselves to depend only on blood measurements.
Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, 90089-9121
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Walter,
Walter Wolf wrote:
> Nick:
>
> In today's reply to Dominique you make a very important point:
>
>> Real pharmacologists (and even toxicologists) should be concerned with
>> concentrations in tissues not doses!
>>
>
> I should make a slight change to that statement:
>
>> Real pharmacologists (and even toxicologists) should be concerned with
>> the rate of change (kinetics) of concentrations in tissues not doses!
>>
>
Perhaps you didn't read the last sentence of my posting which pointed
out the importance of not ignoring time (and this kinetics).
>> This can be understood if you don't ignore time.
>>
However, your proposed change limits the perspective of the
pharmacologist by its emphasis on the rate of change of concentration
and thus its application to pharmacokinetics. Pharmacodynamics is
primarily concerned with the relationship between concentration and
effect when the concentration is not changing. Pharmacology is more than PK!
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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Dear Walter Wolf,
You are very right but i want to know what about the rate of change at Css.
Dr Zafar
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Nick,
The explanation of drug binding to receptor like in a sponge http://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/volume_of_d istribution_ppt.pdf
is what I was pointing out in my precedent email. And for a humble pharmacolgist the concentration in the sponge is what he would like to know. And I appreciate Walter's remark about using now imaging methods that may be more cost effective than blood drawn experiments and expensive analytical methods..
Yes for me drug concentrations at the target tissue is the most important but in fine you have to determine a dose regimen, this was I meant.
To determine you have two approaches:
1- is to use the apparent volume of distribution, the bath tub in your example or
2- to try to access to drug concentration in the target tissue.
As now we are developing drug with very specific targets, the second approach may be more informative in the dose decision making,
Dominique Paccaly
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The following message was posted to: PharmPK
Dear pharmacologists,
Drug distribution, localization of tissue deposition and of specific
target receptor binding, including target kinetics, remains
problematic. It is a long old story. Prof. Wolf's efforts are in the
right direction. A combination of methods is required.
Here is an example: vitamin D has not been found in brain and spinal
cord with common biochemical assays and whole body autoradiography (no
nuclear imaging data are available). By contrast, with the
histochemical Microscopic Receptor Autoradiography maps of target
neurons have been provided - already during the 1980s. Similarly, with
common ADME procedures only low and insignificant amounts of vitamin D
in the stomach have been contradicted with histochemical findings of
specific target cell populations in the isthmus region of gastric
glands, in antrum entero-endocrine cells,and in the pyloric muscle. Fat
cells and skeletal and smooth muscle cells, reported positive for
vitamin D uptake with biochemical radioassays have been found negative
with the microscopic approach. Clearly, there is a need for high
resolution - high sensitive correlative and complementary approaches
and data.
For vitamin D, with the histochemical method multiple targets (over
50!) have been identified and the calcium-paradigm challenged already
20-30 years ago, at a time when the calcium concept with prevailing
'expedient' methods yielded mere 5-10 targets. Only recently a change
in paradigm is slowly progressing, delayed by methods and mindset.
What do we know about the targets e.g., of cardiac glycosides
(Digitoxin) with their many 'side' effects, of acetosalicylic acid
(Aspirin), and other commonly used drugs?
(Memo to the FDA and ICH: appeal for in vivo drug target identification
and target pharmacokinetics. Recommendations for improved procedures
and requirements. Drug Discov Today. 2007 Aug;12(15-16):594-8.)
Walter E Stumpf, Dr.med., Ph.D., Dr.h.c.
Professor of Cell Biology and Pharmacology em.
2612 Damascus Church Rd
Chapel Hill, NC 27516
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Dominique,
Despite the claims made by the imaging marketing teams, the practical way to calculate the loading dose is to use the apparent volume of distribution. I cannot imagine what world you live in that finds imaging techniques are more cost effective than measuring blood concentrations and using simple PK ideas that have been proven many times to predict the right dose to achieve the target concentration.
There are expensive methods that can give clues to receptor occupancy for a very limited class of drugs (e.g. dopamine antagonists). These have been useful to drug developers wanting to know what are likely to be effective doses before they did real studies looking at the therapeutic effects. But once the effective dose has been demonstrated (at great expense) the plasma concentration has just as much information about to predict the relationship between dose and effect site concentration as the high cost imaging methods. In the very rare situations when the plasma concentration is not proportional to the effect site concentration then some other method may be helpful. I have never heard of one but I am ready to be educated.
I look forward to hearing about the evidence for real drugs where the relationship between dose and effect site concentration is not predicted by plasma concentration. My prediction is that the list will be very short compared with the large number of real drugs whose effects (at equilibrium) are related to plasma concentration by simple pharmacodynamic relationships such as Emax or sigmoid Emax models. The technology for accounting for delays between plasma concentration and time course of response has been known for decades so don't bother giving me naive examples which use simplistic statistical methods like correlation coefficients between plasma conc and response that ignore time.
Nick
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The following message was posted to: PharmPK
Nick:
There are few, if any, fields in science where there is one single and universal solution. And let me ask you if you can provide any evidence where the relationship between dose and effect site concentration for anticancer drugs at solid tumors is indeed predicted properly by plasma concentrations only. Anticancer drugs behave differently than antibiotics or drugs acting on diseases of physiological organs. Imaging studies may be of marginal interest, or of no value at all in a number of drug studies. They are of highly significant value in the study of drug targeting and effectiveness (PK/PD) in solid tumors. And they are likely to be also very important in neurological studies, where the blood-brain barrier limits transport from blood to brain tissues.
What is naive is the assumption that one size fits all. Life would indeed be very simple if it would.
Walter
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Hi,
Last week I posted here a URL to material about basic concepts of apparent volume of distribution.
I am afraid some of you may have been made to suffer from a "web-policy" decision at my University that file names must not include "_" but instead use "-". Yesterday all files were renamed so that unfortunately the original URL will no longer work.
However, you can find the volume of distribution file (and others) here:
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci722 /timetable.aspx
The volume of distribution pdf is in the list of resources for the introductory lecture with this URL:
http://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/volume-of-d istribution.pdf
If you still cannot download the pdf then please let me know and I will send it by email.
Best wishes,
Nick
-- Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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Walter,
You ask me to provide evidence where the relationship between dose and effect site concentration for anti-cancer drugs at solid tumors is predicted by plasma concentrations.
I believe evidence can be found in this paper which describes the use of plasma concentrations to predict the effect site concentration of gemcitabine in shrinking solid tumours (lung cancer) in patients. This model, based on the predicted effect site concentration, was able to successfully describe the relationships between dose, plasma concentration and the time course of tumour shrinkage and regrowth after treatment was stopped.
Tham LS, Wang L, Soo RA, Lee SC, Lee HS, Yong WP, Goh BC, Holford NH. A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients. Clin Cancer Res. 2008;14(13):4213-8.
You say that "[Imaging studies] are of highly significant value in the study of drug targeting and effectiveness (PK/PD) in solid tumors.". Please let me have references to these studies where they demonstrate that the information obtained from imaging studies can predict the time course of effectiveness better than a model driven by plasma concentrations.
Because a scientific principle is simple does not mean it is naive. The principle that steady state drug concentration in plasma is proportional to effect site concentration is a simple and powerful one. I am not aware of any exceptions. If you know of any I would be glad to hear of them.
Nick
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Nick:
Sorry for my delay in answering your e-mail of 8/16/10, but I just finished attending 3 sets of all day retreats that preceded our starting the Fall semester classes next week.
In your prior e-mail you referred to one of your papers where indeed there was a relationship between plasma level and tumor shrinkage. Nice paper, and the data for that one example appear convincing.
You then asked me to give you references where imaging studies can predict the time course of effectiveness better than a model driven by plasma concentrations.
Here are two from our work:
Noninvasive Studies of Fluoropyrimidines. Walter Wolf, Cary A. Presant and Victor Waluch. Chapter 9 in Fluoropyrimidines in Cancer Therapy. Youcef Rustum, editor. In: Cancer Drug Discovery and Development series, Humana Press. Totowa, NJ, 2002.
and
Does Leucovorin Alter the Intratumoral Pharmacokinetics of 5-Fluorouracil (5-FU)? A Southwest Oncology Group Study. Cary A. Presant, Joth Jacobson, Walter Wolf, Victor Waluch, Ilene Weitz, and John Macdonald, Investigational New Drugs 20, 369-376, 2002.
And there are NO studies showing a relationship between plasma levels of 5FU and tumor shrinkage.
The bottom line is that there is NO single method that answers all PK/PD questions. Traditional blood levels may answer many, but not all. Noninvasive imaging, a much more recent technique, is proving highly useful in some studies, but certainly is not a panacea for all PK/PD studies. Both approaches can provide unique and important answers, and we must keep an open mind which technique is most suitable for answering each specific problem.
Walter
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