Window of absorption

From: majid.vakily@tap.com Subject: [NMusers] Window of absorption Date: Mon, March 28, 2005 2:56 pm Hi, I am trying to do POPPK analysis for a drug with a window of absorption. The absorption from GI tract is initially slow and then there is a sudden increase in the plasma concentrations. Therefore, the absorption phase has two rate constants slow and rapid. I should also mention that the drug follows a compartment open model with a first order inputs and first order output processes. Is there a NONMEM subroutine for the window of absorption phenomenon?I have tried ADVAN 6 with differential equations. However, it is very slow. I appreciate any input about this issue and perhaps an example of control stream with statement for switching from the first absorption rate constant (Ka1, occurs earlier in profile and completed within 30 minutes) to the second absorption rate constant (Ka2, larger of two constants which may represent the optimal absorption site). Regards, Majid Vakily, Ph.D. Senior Research Investigator Department of Drug Metabolism & Pharmacokinetics Phone: (847) 582-2198 Fax; (847) 582-2388

From: majid.vakily@tap.com Subject: Re: [NMusers] Window of absorption Date: Mon, March 28, 2005 4:10 pm Hi, Sorry, the drug follows 2 compartment model. Regards, Majid Vakily, Ph.D. Senior Research Investigator Department of Drug Metabolism & Pharmacokinetics Phone: (847) 582-2198 Fax; (847) 582-2388

From: "Gordi, Toufigh" Toufigh.Gordi@cvt.com Subject: RE: [NMusers] Window of absorption Date: Tue, March 29, 2005 1:20 pm Dear Majid, Two solutions come in my mind. Before describing them, let me just warn you that I have no experience with such a system and my proposals (specially the second one) might not work. Here they come: - Construct an absorption system with at least 2 compartments, similar to a transduction PD model, where you have the drug administered into the first compartment. Initial condition for the second compartment is equal to 0. The compound leaves the first compartment via 2 routs: absorption to the central compartment and transfer to the second absorption compartment. You may want to test whether a single KA will work for both compartments or if you need different ones for each absorption compartment. - Write an IF...THEN statement, where you have a KA until a certain time and another KA after that. As I said, I would start with the first option, as it is more close to what happens in reality: you have a transfer of your compound through the GI track with different segments having different absorption capacities. Toufigh

From: majid.vakily@tap.com Subject: RE: [NMusers] Window of absorption Date: Tue, March 29, 2005 1:28 pm Dear Gordi, I have already tried the second option. I have if and then statements for the first and the second absorption rate constants with switch from Ka1 to Ka2 occurring at 0.5 postdose (based on deconvolution results). The program seems working fine, however, it is taking too long to converge. I started the run approximately 40 hours ago and run still going. Do you know any subroutine already in NONMEM library to speed the process up or I do have to use differential equations in ADVAN6. Best Regards, Majid Majid Vakily, Ph.D. Senior Research Investigator Department of Drug Metabolism & Pharmacokinetics Phone: (847) 582-2198 Fax; (847) 582-2388 _______________________________________________________