Modeling of iv and po data

From: "Gordi, Toufigh" Toufigh.Gordi@cvt.com Subject: [NMusers] Modeling of iv and po data Date: Wed, August 11, 2004 4:31 pm Dear all, I am trying to model data from a study including both iv and po data. The bioavailability is quite low (~15%). The highest po doses given were 10 times higher than the highest iv dose. When modeling the iv data alone, a non-linear CL gives the best fit. Such a model, however, does not converge when iv and po data are combined. The major problem, I believe, is the estimation of ka. Any suggestion on how to proceed? And in general, if one of the characteristics of the model including iv data (let's say the non-linear CL) is masked by the PK profile after po, what would be the best approach to model the data? Model the data separately or apply a simpler model to the combined data set? best wishes, Toufigh Gordi

From: Nick Holford n.holford@auckland.ac.nz Subject: RE:[NMusers] Modeling of iv and po data Date: Wed, August 11, 2004 4:54 pm Toufigh, If you have mixed order elimination detectable from the IV dose then it is quite possible that you will have rate dependent first pass extraction with the oral dose e.g. see Holford NHG. Complex PK/PD models - an alcoholic experience. International Journal of Clinical Pharmacology and Therapeutics 1997;35(10):465-468. I would not worry about lack of convergence until you have got a good handle on the structural model. In the end the visual goodness of fit of the observed and predicted values and perhap a simple predictive check (simulation from your final model) are more meaningful than NONMEM's semi-arbitrary decision to declare 'convergence'. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ _______________________________________________________