- On 8 Dec 1997 at 14:07:47, Roger Jelliffe (jelliffe.-a-.hsc.usc.edu) sent the message

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Dear David:

Why do you feel the need to do all this tramsformation? And why do you

assume constant CV? Is that for the lab errors? And if so, why?

I think there are 2 issues here - one concerning the credibility of lab

(serum) assays. The other is to suggest that you might consider a method

such as nonparametric population modeling, in which no parametric

assumptions need to be made about the shape of the distribution of the

parameter values, such as normal, lognormal, etc..

It is useful, and optimal, to give weight to serum level data

according to

its Fisher information - weighting by the reciprocal of the assay variance.

This is usually not done, and people weight by 1/C or 1/Csquared, unity

weighting, and other ways which really are not very realistic, as most

assays do not have a constant CV. This is discussed in part in Ther. Drug

Monit. 15: 380-393, 1993.

The other issue is that of nonparametric population modeling. A useful

reference is by Schumitzky, in Applied Math + Computation, 45: 143-157, 1991.

The bottom line of all this is that one wants to give weight to

each data

point according to its information content, and that one wants to find the

joint probability density that has the greatest likelihood given the doses

and the concentration data. The reason for this is that one wants THEN to

be able to develop the dosage regimen (for the patient, as well as for the

FDA) that MOST PRECISELY hits the desired target therapeutic goal selected

by the clinician for each patient according to his need for the drug. This

precision is provided by the natural link between nonparametric population

modeling and the "Multiple Model" method of dosage design, which can be

done specifically, for example, to minimize the expected value of the

weighted squared error with which a desired target goal is achieved by the

regimen. A useful reference here is by Bayard, Milman, and Schumitzky in

Int. J. Biomed. Computing, 36: 103-115, 1994.

All this is different from most of the approaches currently used, but I

would suggest that it is worthy of your consideration.

Very best regards,

Roger Jelliffe

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

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.-at-.hsc.usc.edu

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