modelling strategy question

Hi all, I have the following issue. Maybe someone has a helpful hint? Data of a human cross over study (dense sampling) on the absolute bioavailability are to be modeled using NONMEM. In one period the drug is administered i.v., in the other s.c.It turns out that after the s.c. administration the kinetics follwo a 1-cmt model, while after the i.v. administration a 2-cmt model is observable (in each case quite clearly). Can anybody recommend how to fit that situation simulatneously? Thanks in advance, Emily

Emily, Standard PK theory for linear models proposes that the distribution and elimination processes are independent of input. It is well recognized that if the input is slow (e.g. after SC dosing) that it may be difficult to discern a fast distribution phase so that a one compartment distribution model will fit the data as well as a two compartment model. The rejection of a two compartment model on statistical grounds should be seen as a limitation imposed by the data and not invalidation of standard PK theory. I suggest you fit the data simultaneously using a two compartment distribution model e.g. using ADVAN4. This will allow you to use a first-order input of the SC dose into a depot compartment (CMT=1) and a direct input of the IV dose.into the central compartment (CMT=2) . The SC input will distribute into a 2 compartment system as determined by the IV data. You will need to use the CMT data item to signal to NONMEM which compartment the AMT is to be put into depending on the route of administration. Best wishes, Nick