RE: metabolite modeling

From: "Leon Aarons" <laarons@fs1.pa.man.ac.uk> Date: Mon, 13 Dec 1999 12:23:37 GMT Subject: RE: metabolite modeling I agree with Mats that the metabolite data can support the drug data, if for no other reason that effectively the number of degrees of freedom are increased. However I would inject a note of caution. A number of years ago we did some nonlinear regression modelling on lignocaine (or lidocaine depending on which side of the Atlantic you come from) (P.N.Bennet, L.J. Aarons, M.R. Bending, J.A. Steiner, M. Rowland, 'Pharmacokinetics of lidocaine and its de-ethylated metabolite: dose and time dependency studies in man', J.Pharmacok.Biopharm. 10, 265-281 (1982)). The fit to the drug data (iv) was good. When the iv and oral data were fitted simultaneously they both looked lousy. By deconvolution the problem was found to be the link between the iv and oral data. In this case a simply time delay sufficed to correct the problem and, to be fair, the simultaneous fit did add something. The same thing can happen with simultaneous drug & metabolite modelling. If the link between drug and metabolite is not correctly specified, then the fit to the drug will suffer, for the reasons mentioned by Mats. So although there are advantages to simultaneous fitting, the link between drug and metabolite needs to be carefully investigated. Sequential fitting would seem a sensible first alternative and deconvolution, if possible is also useful. __________________________________________________ Leon Aarons School of Pharmacy and Pharmaceutical Sciences University of Manchester Manchester, M13 9PL, U.K. tel +44-161-275-2357 fax +44-161-275-2396 email l.aarons@man.ac.uk