RE: Autoinduction

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com> Subject: RE: Autoinduction Date: Wed, 16 May 2001 08:48:37 +0200 Sreenivasa, You modified already your control compared to the yesterday version, particularly, you excluded DV from $DES block. There are still a few issues that may cause problems: 1. An enzyme submodel. I prezume the enzyme should have some steady-state level which is altered by the drug. There should be a formation rate for the enzyme not equal to KENZ, say KIN. The baseline amount of enzyme is then KIN/KENZ. 2. Initialization of compartment 4. I think you do not need $AESINITIAL. You have to introduce a unit amount into COMP 4 at TIME=0 using an extra dose record in your data set. 3. In your model, the enzyme has no impact on the drug elimination. In the framework of the autoinduction model CL should depend on the enzyme amount. Have a look at the following recent publications: 1. Hassan M. Svensson USH. Ljungman P. Bjorkstrand B. Olsson H. Bielenstein M. Abdel-Rehim M. Nilsson C. Johansson M. Karlsson MO. A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. British Journal of Clinical Pharmacology. 1999; 48(5):669-677. 2. Kerbusch T. Huitema ADR. Ouwerkerk J. Keizer HJ. Mathot RAA. Schellens JHM. Beijnen JH. Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM. British Journal of Clinical Pharmacology. 2000; 49(6):555-561. Best regards, Vladimir