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The following message was posted to: PharmPK
I would be grateful for any help regarding dose adjustment of methotrexate.
We currently use 8g/m2 for the treatment of osteosarcoma but are interested
in a method for adjusting doses to achieve a peak serum level of 1umol/l.
I am aware of publications in the literature using Bayesian estimation of
parameters but am looking for a practical method for use in the clinical
setting.
Many thanks
Simon Rivers BPharm MRPharmS
Senior Oncology Pharmacist
Velindre NHS Trust
Cardiff UK
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Simon,
The third edition of Winter's Basic Clinical Pharmacokinetics has
some practical information on how to dose methotrexate. The salient
pharmacokinetic data are:
Cl= 1.6(Clcr)
MTX concentration in 10-6 molar= (MTX concentration in mg/l)/(.454)
Cpssave= FSD/(Cl)(Tau)
Vd for loading doses = .2-.5 L/kg
T1/2 for concentrations> 5 x10-7 molar= 3 hours
T1/2 for concentrations< 5 x10-7 molar= 10 hours
So, using the above data, the mg dose to achieve 10-6 molar in a
70kg patient is:
[Loading dose/Vd]= 10-6 molar= (.454 mg/ml)
[Loading dose/(.375 l/kg X 70kg] = (.454 mg/l)
Loading dose= (.375 l/kg x 70kg)(.454 mg/l)= 11.92mg
There are also 23 journal articles cited as references.
Mike Leibold, PharmD, RPH
ML11439.-a-.goodnet.com
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Dear Simon,
We are using for years bayesian estimation for dose adjustment of high dose
MTX at the Hopital de la Timone, Marseille, France.
We use the APIS software and a population , unfortunately never published
but in french journals (if you read french: J. Ciccolini et al., Journal de
Pharmacie Clinique, 15(1), 3440 1996 or ask us a reprint ).
Briefly, MTX is administered I.V continuously for 8 hours. The
administration is standard up to 6 hours, and the dose from 6 to 8 hrs is
adapted from 2 sampling points (3.5 and 4.5 hrs) and the population
parameters to achieve a Cmax of 10-6 M or 0.5 10-6M according to the patients.
If you need further informations about this method, Apis software or the
population characteristics, please let me know.
Alternatively, you can get in touch with Dr. Monjanel, she is in charge
with MTX bayesian adaptation: suzanne.monjanel.aaa.pharmacie.univ-mrs.fr.
I hope this helps, what the hell have you done during the last Euro2000?
Pr. Jacques Catalin, Ph.D.
Laboratoire de Toxicocinetique et Pharmacocinetique
Faculte de Pharmacie
27, Bd Jean Moulin
13385 Marseille cedex 05
France
Phone: (33) (0)4 91 83 55 09
Fax: (33) (0)4 91 83 56 67
http://www.multimania.com/pharmapk/
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To the PharmPK list,
In a framework of an international cooperation, we are involved in dose
adjustment of methotrexate (MXT) in clinical use, aimed to
determine dosing of MTX for an individual patient.
Basically, there are the following situations:
1) A test dose of MTX is given in a single dose to an individual
patient, the concentration-time profile of MTX is measured in the patient,
and this profile is used to identify the model describing the behavior of
MTX in this patient. After that, this model is used to calculate
loading and maintenance doses of MTX, necessary to reach and maintain
required trough levels of MTX in this patient at desired time points,
both (the levels and time points) specified by treatment requirements.
2) In the first step, dose adjustment is the same as that described
abowe. Then, the concentrations of MTX are measured also at particular time
points during the treatment. The goal is to modify step by step the model
parameters and dosing according to the changes in the processes dominant of
the behavior of MTX in the patient, which may occur during the long time
period of the treatment.
3) The concentration-time profile of MTX after a test dose
of MTX is not available for a given patient. In this situation,
the concentration-time profiles of MTX of a group of similar patients
can be used to identify a model describing the behavior of
MTX and to adjust dosing of MTX (as described in paragraph 1).
After that this model is modified step by step using the
measurements of the concentration of MTX in this patient
during the treatment (as described in paragraph 2).
Accuracy of dose adjustment of MTX is dependent on accuracy of the model
describing the behavior of MTX. According to our experience, the models
determined by the frequency response method yield good results. This
method is described in our studies listed at the www page given below.
With best regards,
Ladislav Dedik
and
Maria Durisova
Dipl. Engineer Maria Durisova D.Sc.
Senior Research Worker
Scientific Secretary
Institute of Experimental Pharmacology
Slovak Academy of Sciences
SK-842 16 Bratislava
Slovak Republic
http://nic.savba.sk/sav/inst/exfa/advanced.htm
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Ladislav & Maria
Typically the test dose for MTX is quite low - and some
portions of the conc-time course may be difficult to
characterise or inaccurately characterised due to assay
limit problems. So when you dose based on this model - how
do you assess the generality of the recommendation to higher
doses in the same patient? I can understand how you might
do this if you assume the same model for everyone in the
population and then "just" estimate the parameter values for
each individual patient (such as may be done in a so-called
Bayesian MAP sense). Then in step 2 you say you modify the
model parameters based on feedback from the second dose -
but what if the model characterised in part 1 for this
patient was wrong ... does your system allow you to modify
the model?
Have I interpreted you correctly? What is your experience
wrt model misspecification?
Regards
Steve
=================
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane, QLD 4072
Australia
Ph +61 7 3365 8808
Fax +61 7 3365 1688
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