- On 14 Aug 1997 at 12:34:01, jgomez1.at.nemak.com sent the message

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Im an applied statistical student and Im very interested in random

coeficients models to estimate the dosage parameters.

How many methods exist to calculate the dosage of a given drug for a given

patient?

Please send any references to

jgomez1.aaa.nemak.com

Thanks. - On 15 Aug 1997 at 10:36:29, Roger Jelliffe (jelliffe.-a-.hsc.usc.edu) sent the message

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Dear Jose Luis:

Probably most methods use conventional PK models and simply compute the

dose needed to achieve a desired target peak or trough value. In addition,

some do this to achieve desired target concentrations in the peripheral

(nonserum) compartment of a patient's PK model. A review can be found in

Therapeutic Drug Monitoring 15: 380-393, 1993, and in Int. J. Biomed

Cumputing, 36: 1-23, 1994. These are all based on Maximum Aposteriori

Probability (MAP)Bayesian approaches to adaptive control of dosage regimens

using parameteric PK models in which the parameters have only a single

value (ie, the Vd is xxx and the Kel or clearance is yyy. etc.).

Another approach to computing dosage regimens is the "Multiple Model"

approach. it is based on nonparametric PK models. Each parameter has many

possible values. The nonparametric maximum likelihood (NPML) approach of

Mallet is one such approach. This is described in Mallet A: A maximum

likelihood regression estimation method for random coefficient regression

models, in Biometrika, 73: 645-656, 1986. It is reviwed by Steimer JL,

Mallet A, and Mentre F in: Estimating Interindividual Pharmacokinetic

Variability, in Variability in Drug Therapy: Description, Estimation, and

Control, ed by Rowland M, et al, Raven Press, New York, pp 65-111, 1985.

Another nonparametric approach is the nonparametric EM (NPEM)

approach of

Schumitzky, as described in Nonparametric EM Algorithms for Estimating

Prior Distributions, in Appl. Math. Comput. 45: 143-157, 1991.

Both methods of population modeling are well suited to the multiple

model

(MM) control approach The NPML method has been used with MM control by

Taright et al, Therapeutic Drug Monitoring 16: 258-269, 1994.

The NPEM models have been used in MM approaches by Bayard, Milman, and

Schumitzky, in Int. J. Bio-Med Comput. 36: 103-115, 1994, and descdibed in

more detail in a chapter in Selected Topics in Mathematical Physics

(Professor R. Vasudeval Memorial Volume) ed by Sridhar, Rao, and

Lakshminarayanan, Allied Publishers Ltd, Madras, pp 407-426, 1995. A

clinical version of this approach is now in development.

Since multiple versions (models) of the patient are present, a

candidate

regimen can be developed. It will predict a trajectory of serum levels into

the future for each model. These predicted concentrations can be compared

with a desired concentration at a desired time, and a penalty function such

as a weighted least squares one can then be minimized, thus choosing the

regimen which specifically minimizes the penalty function. This method,

therefore, can conside the cost or penalty of not achieving the desired

goal (a feature not possible with parametric models), and can specifically

compute the dosage regimen which most precisely achieves the desired goal.

************************************************

Roger W. Jelliffe, M.D.

USC Lab of Applied Pharmacokinetics

CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033

Phone (213)342-1300, Fax (213)342-1302

email=jelliffe.-a-.hsc.usc.edu

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