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From: Kazimierz H. Kozlowski, Pharm. D.
Laboratory of Clinical Pharmacology
The Children's Memorial Health Institute
04-736 Warsaw, POLAND
E-mail: khkoz.-at-.czd.waw.pl
Dear all,
Cystatin-C serum level is suggested as new, better than creatinine
clearance, biomarker for GFR
in newborns and infants.
I have developed population PK model for gancyclovir in CMV-infected
newborns and infants.
Elimination rate constant was initialy modeled as nonlinear function of
creatinine clearance.
Cystatin-C measurements seems be more convenience (specific, not need
anthropometry or scaling).
I have submited new project for ganciclovir and Cystatin-C.
Does anyone have experience with Cystatin-C as a covariate for any drug
clearance model.
sincerely
Kazimierz H. Kozlowski
Literature:
(1). Cystatin C. The most sensitive marker for assessment of the
Glomerular Filtration Rate(GFR). Dade Behring, 1999.
1/cystatin C vs GFR (n=51, r=0.87) acc.to Jung K., Jung M.: Nephron
1999, 70, 370-371.
1/creatinine vs RFR (n=51, r=0.71)
1/cystatin C vs 1/creatinine (n=51, r=0.73)
(2). Catalgi L., Mussap M., Bertelli L., Ruzzante N., Fanos V., Plebani
M.: Cystatin C in healthy women at term pregnancy and their infant
newborns: relationship between maternal and neonatal serum levels and
reference velues. Am. J. Perinatol. 16, 287-295, 1999.
(3). Fanos V., Mussap M., Plebani m., Cataldi L.; Cystatin C in
paediatric nephrology. Present situation and prospects. Min. Pediat. 51,
1-8, 1999.
(4). Finney H., Newman D.J., Thakkar H., Fell J.M.E., Price C.P.:
Reference ranges for plasma cystatin C and creatinine measurements in
premature infants, neonates, and older children. Arch. Dis. Child. 82,
71-5, 2000.
# Cystatin C offers a more specific and practical measure for monitoring
GFR in the paediatric population than does creatinine.
# Cystatin C is a better marker than creatinine of glomerular filtration
rate (GFR) in preterm infants.
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Hello,
My comment is not directly related to your question. It might be more
meaningful to model the clearance (which is a fundamental PK property of
any drug) as a function of any covariate rather than the elimination
rate constant (which is a secondary parameter).
Regards,
Joga Gobburu
Pharmacometrics,
CDER, FDA.
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Dear Joga:
Since when is clearance a fundamental PK property of a drug?
Since when is the elimination rate constant a secondary parameter?
Why is this? I would very much like to know. What do we really know
about the behavior of drugs in general? Why does the "fundamental"
property of clearance appear to get forgotten when we go to big
models with many compartments?
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.at.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
769 7329671
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Dear Roger,
I am a bit puzzled to see your questions. But it seems as if you have
reservations in accepting clearance as a fundamental property of drugs.
Please find my replies to your questions below.
> Since when is clearance a fundamental PK property of a drug?
(You probably meant 'Why' and not really 'since when')
The two basic properties of any given organ are its function and size.
Clearance (CL) which reflects the 'function' and volume of distribution
(V) which reflects the size of the organ(s),are the two fundamental
properties of a drug.
Eg: CL: GFR=120 mL/min and blood flow thr' liver is 90 L/h.
(normal adult)
V : total body water=58% of body weight (normal adult).
extracellular fluid=4% of body weight (normal adult).
>Since when is the elimination rate constant a secondary parameter?
Rate constant for the elimination (Kel) of any drug is a function of the
clearance (CL) and the volume of distribution (V). And not the other
way. Hence if one tells me that there is 60% variability in Kel, I am
not sure how to interpret that from a mechanistic point of view. I would
not be able to meaningfully explain this variability by including some
covariates (eg: renal function, binding, etc).
>What do we really know about the behavior of drugs in general?
It is hard for me to guess what you really mean by this question. We
have a long experience understanding/modeling PK of drugs and using this
knowledge to design and analyze PK data and propose dosing regimens.
> Why does the "fundamental" property of clearance appear to get
>forgotten when we go to big models with many compartments?
The 'big' models like the physiologically based PK models indeed use
the fundamental properties such as: blood flows, partition coefficients
and volumes of organs to describe the kinetics of drugs.
Regards,
Joga Gobburu,
Pharmacometrics,
CDER, FDA.
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Dear Joga:
Thanks again for your second thoughtful note. About your
point #1, if it is physiologically meaningful "to you" to look at the
CL and V, that is fine, for you About your point #2, if the apparent
clearance of a drug is similar to the GFR, it may be naive to assume
that this is really so, and it needs to be proven . A similar
illusion has been the V of aminoglycosides being similar to the
extracellular fluid volume, thus making people think it is not taken
up into cells or tissues. If you are interested in the behavior of a
drug that may have a certain renal excretion, then that is what must
be explicitly examined, and the relationship between either K or CL
and CrCl or GFR is what must be examined. If your preference is for
clearance, as you have said, then that is fine. However, that is not
a fundamental property of the drug.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-at-.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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Roger,
"Roger Jelliffe (by way of David_Bourne)" wrote:
> If your preference is for
> clearance, as you have said, then that is fine. However, that is not
> a fundamental property of the drug.
There are 2 elementary equations in pharmacokinetics:
Amount = Volume x Conc
Rate = Clearance x Conc
The parameters volume and clearance are quite independent parameters
describing the interaction of the body and the drug.
From a practical perspective they are of basic importance because
they provide the key for predicting loading dose and maintenance dose
rate.
Loading Dose = Volume x Conc
Maintenance Dose Rate = Clearance x Conc
What could be more fundamental?
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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