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Andreas,
The usual initial oral dose of cyclosporine is ~15mg/kg/day given
as a single daily dose or as a divided dose every 12 hours. If oral
administration is not possible, cyclosporine can be given IV at
about one-third of the oral dose (~5mg/kg/day) since the oral
bioavailability is about 30%.
For living donor kidney recipients, cyclosporine is given 1-2
days before transplantation to achieve therapeutic concentrations
at the time of transplantation. Oral or intravenous doses are
adjusted using trough levels according to the therapeutic range
for the particular assay being used (Table 1). Blood samples for
cyclosporine analysis should not be drawn from the same IV line
used to administer the drug. Patients can be changed to oral from
IV cycloporine therapy be giving three times the IV dose orally
since the bioavialability is only 30%.
Table 1 The Therapeutic Range for Cyclosporine by Assay
Assay Serum Plasma Whole Blood
(ug/liter) (ug/liter)
Monoclonal Radio 50-125 150-400
Immunoassay
Florescence Polari-
zation Immunoassay
Polyclonal 150-400 200-800
Monoclonal 50-125 150-400
High-performance 50-125 150-400
liquid Chromatograpy
The population pharmacokinetic parameters of cyclosporine have
been published in several references (1-3) and are summarized in
Table 2. As with the therapeutic range, the pharmacokinetic parameters
can vary with assay and biological fluid used. The clearance of
5-10 ml/min/kg indicates that it is probably a low extraction drug
whose elimination depends on the unbound fraction in the blood:
Cls= FuCli
Cls= systemic clearance
Fu= fraction unbound (< 0.1)
Cli= intrinsic clearance or metabolic capacity
Cycloporine is metabolized almost entirely by hepatic metabolism
with subsequent biliary and urinary elimination.
Table 2 Cycloporine Pharmacokinetic Parameters
Bioavailability(F) 30%
Volume of Distribution(Vd) 4-5 l/kg
Clearance (Cl) 5-10 ml/min/kg
Half-life(T1/1) 6-12 hours
Free Fraction(alpha) <10%
Trough levels are generally used for pharmacokinetic dose
adjustment, since peak levels are variable due to uncertain
absorption properties. When therapy is initiated, cyclosporine
levels are generally taken every other day until a stable steady-
state level is obtained. In stable hospitalized patients, levels
are usually taken every 5 days, as compared to every 30 days in
stable outpatients. The goal of therapeutic drug monitoring is
to achieve therapeutic concentrations while avoiding nephro-
toxicity. Low-risk patients (eg HLA identical grafts) may receive
higher doses than high-risk patients (poorly HLA matched grafts).
Pharmacokinetic dose adjustment can accomplished with computer
programs or with any calculating device, with similar results. The
pharmacokinetic model assumed is a one compartment linear model:
Cssave= FSD/[(Tau)(Cl)] Equation 1
Probably most dosage adjustments can be performed using
the following equation (derived from the above)(1):
Equation 1A
Desired dose= [(Cpss desired)/(Cpss Current)] x Current Dose
However, in diificult cases, it may be necessary to calculate
the elimination constant and adjust the dose based on this. Equation 3
may be used to calculate the elmination constant, and then equation 5
may be used to calculate the dose based on the Ke and the desired
Cminss and Tau(1).
Cminss= [FSD/Vd]e-KTau/[(1-e-KTau)] Equation 2
Cmaxss= [FSD/Vd] + Cminss Equation 3
K= Ln(Cp1/Cp2)/(Time)=
Ln(Cmaxss/Cminss)Tau=
Ln([FSD/Vd + Cminss]/[Cminss])/Tau Equation 4
Dose= (Cminss)(Vd)(1-e-KTau)/[(S)(F)(e-KTau)] Equation 5
F= 0.3 (fraction absorbed
S=1 (fracton of salt form active drug)
Vd= 4.5 L/kg X body weight(Kg)
Tau= Dosage interval in hours (12 hours usually)
Cminss= trough concentration in ug/liter
Summary:
Basic Clinical Pharmacokinetics (1) might be a good reference for
you, since the author clearly explains the above equations. The simple
equation 1A should accomplish most of your dose adjustments, while
the clinical details (including the assay type) should provide most
of the challenge. How your assay agrees with those of Table 1 would
be an important issue to resolve before you consider a computer program.
A dosage adjustment algorithm which includes scenarios of cyslosporine
nephrotoxicity, graft rejection, malabsorption and poor compliance is
available in Applied Pharmacokinetics (3).
Mike Leibold, PharmD, RPH
ML11439.-a-.goodnet.com
References:
1) Winters,M.E., Basic Clinical Pharmacokinetics 3rd ed., Vancouver,
Applied Therapeutics 1994;185-197
2) Schumacher, G.E., Therapeutic Drug Monitoring, Norwalk, Appleton&
Lange 1995;449-468
3) Evans, W.E., Schentag, J.J., Jusko, W.J., Applied Pharmacokinetics
3rd ed.,Vancouver, Applied Therapeutics 1992;(28):1-40
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Mike,
thank you for your friendly answer.
Today was the first meeting between a participating persons in our project
- the physician, the clinical lab and the pharmacy.
I am convinced that the physician has almost no knowledge about
pharmacokinetics. He said all dose adjustments he ever has made was
because of experience ( I would say try and error ).
So there will be enough for the pharmacy to do to help getting faster
into the steady state.
Do you know some pharmacists working on a transplant station and do
the dosage regimen design as their every day job ? I think that wolud
be helpful too.
With best regarding,
Andreas Rutz
Hospital Klinikum rechts der Isar, Muenchen
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Dear Andreas Rutz:
It was interesting to see your note in the PharmPK. You are right -
physicians usually have no knowledge of PK. It is never taught to them. The
fault is the curriculum committees that remain uninterested in it, and the
basic science pharmacologists who think PK is some sort of a dry science
rather than a useful clinical tool, which they do not know how to use. As a
result, physicians are taught to become robots and to follow what someone
has said in a book about patients in general and therapeutic ranges in
general. How can such a person know your patient better than you? Why do we
teach physicians to turn their eyes away from their patients and learn some
ritual from a book, rather than teaching them how to become good therapists
and optimal managers of their patients problems in drug therapy?
So much for THAT. I would be very interested in working with you on
problems of optimal drug therapy in transplant situations. There is a great
need for modeling and optimal management of drug dosage for them. You might
also consider an article by our group in Clinical Pharmacokinetics, 34:
57-77, 1998, on Model-Based, Goal-Oriented, Individualized Drug Therapy. I
would look forward eagerly to talking with you more.
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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Andreas,
We are working with bayesian forecasting to individualise dosage in
immunsuppresvie therapy on a consultant basis. If you are looking for
further input for deciding what pharmacokinetic model to use for
cyclosporine, I would suggest that you read an article by Guang Wu et
al. in Pharmacological Research, vol.34, p.47-57. In our own operation
we have chosen to use a two-compartment model to describe the
pharmacokinetics of cyclosporine. For tacrolimus we have found a
two-compartment model to be more suitable.
I understood that you had concerns wether a one-compartment model would
be
able to take account for the large inter- and intravariability of the
drugs parameters.
if the model is correct,there would be no problems to use a
one-compartment
model, but if the pharmacokinetics is better described by a two-or
three-compartment model, the one-compartment model would of course not
be able to predict the variability.
If you are looking for suitable software for bayesian forecasting in
such a service you are describing, I would suggest you looked at
AbbottBase from Abbott Laboratories or MW Pharm from MediWare. Even
though it is older, AbbottBase is
a bit easier to use, and appear a bit more "honest", beacause of the
rather good
documentation of the software. MW Pharm might use a bit more accurate
weighting
factors, but on the other hand don=B4t have features such as time
weighting of data or
out-patient factors.
Regards,
Johan Wallin
________
Johan Wallin,
CLIPS (Clinical Pharmacokinetic Services AB)
Postal adress: Hamnesplanaden 5 31
=20 S-753 19 Uppsala
=20 Sweden
Phone: +46-(0)18-15 84 15
E-mail: johan.wallin.-at-.clips.se
____
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