Implementation of concentration dependent “first-pass” models using NONMEM

Authors: Phillips L, Cox SR
Conference: AAPS
Division: Cognigen


The development of drugs extensively metabolized by the P450 enzyme system may require the need to model concentration dependent ‘first-pass’ effects. This simulation study, performed using NONMEM, presents two types of concentration dependent ‘first-pass’ models that might be used for drugs extensively metabolized by P450 enzymes located in the intestine. As shown in Figure 1, both models assume a non-linear concentration dependent ‘first-pass’ effect coupled with linear absorption and a combination of Michaelis-Menten (M-M) and linear elimination. The first model incorporates the ‘first-pass’ effect as a loss from the dose compartment and is implemented, using equations specified in the $DES block in the control stream. The second model assumes the ‘first-pass’ effect occurs instantaneously by making bioavailabilit? a non-linear function of concentration. This model is implemented m NONMEM with verbatim code in the $ERROR block of the control stream and by modifying the dosing record structure of the database. The behavior of the two models was simulated over several days of  dosing using a range of values for Ka, Ke, and Vm, Km (M-Mparameters). The simulations showed the most notable difference . m the behavior of the two models to be in the relative approach of Cmax and Cmin to steady-state. The control streams for model implementation in NONMEM will be presented.

American Association of Pharmaceutical Scientists (AAPS); Seattle, Washington; 1996

By Luann Phillips, SR Cox