RE: Fx

From: Xiao, Alan alan_xiao@merck.com Subject: RE: [NMusers] Fx Date: Wed, May 26, 2004 8:23 am Paul, I believe F2 can not help you in your case. Parameter identifiability (or overparameterization) problem related to modeling metabolite (or multicompartment) data, when neither excretion data is available nor separate metabolite administration is conducted, could be fixed by fixing the metabolic ratio. This metabolic ratio could either be from prior studies or derived from preclinical data or derived from other drugs with similar molecular structure and/or similar metabolic pathways. When your system is linear in PK, you could directly fix the metabolic ratio through K values, such as K23/(K20+K23). If your system is nonlinear, you might want to add an excretion compartment and fix the ratio at some value at time infinity (theoretically). If your metabolism is reversible directly or indirectly, the equation to express the metabolic ratio will be a little bit more complicated. By the way, although your metabolic ratio is fixed, the interindividual variability could still be estimated if it's estimable from the data. Whether you use volume of distribution or not in your $DES will not change anything. It's just a matter of reparameterization in the mass balance differential equations. However, if you fix the volume of distribution to a certain value, you might want to be careful because it could be misleading. On the other hand, I doubt you could really solve the overparameterization problem by fixing the volume of distribution. The reason is simple, control volume of distribution can not control the metabolic ratio (or relative mass transport in terms of mass balance). S3 should be scaled consistently as S2 for the purpose of mass balance. Just one point, if your metabolite concentration and parent drug concentration are expressed in weight unit such as ng/mL, you need set up a reference for both using their molecular weight to calibrate their concentrations. Hope this helps. Alan