RE: Modelling intracellular and plasma data

-----Original Message----- From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Rob ter Heine Sent: Tuesday, December 09, 2008 8:28 AM To: [email protected] Subject: [NMusers] Modelling intracellular and plasma data Dear all, I'm trying to fit concentrations of a drug simultaneously measured in plasma as well as intracellularly (in peripheral blood mononuclear cells). I observe a high accumulation in cells, but with a delayed absorption. I'm trying to fit the intracellular data dependent of the plasma pharmacokinetics. The volume of distribution of the cellular compartment can be considered negligeble compared to the volume of distribution in plasma (no distribution to a second compartment can be observed in the plasma pharmacokinetics. However, cellular accumulation depends on plasma concentrations. I'm fitting the data with a first order oral absorption and elimination, basically it can be summarized as: $Model (DOSE) (CENTRAL) (CELL) I have a rich sampling dataset of 11 individuals with at each timepoint an observation in the cellular and plasma compartment. I have tried several approaches for modelling cellular accumulation. I have tried fixing the cellular volume to a very small volume. $PK k12=theta(1) v1=theta(2) cl=theta(3) k20=cl/v1 v3=0.0001 k23=theta(4) k32=theta(5) This didn't work. K23 was estimated to be very small and k32 was estimated to be very large, giving the same fit as estimating an accumulation ratio, which is not a good fit, since a delayed absorption in the cellular compartment was observed. There is some mass transport going on between the central and cellular compartments, that I do not want. My cellular pharmacokinetics depend on the plasmapharmacokinetics, but I don't want my cellular pharmacokinetics to influence my plasma pharmacokinetics, since this effect is likely negligible. Does anyone have a smart idea on how to code this? Sincerely, Rob ter Heine _______________________________ Rob ter Heine, MSc, PharmD Department of Pharmacology, Slotervaart Hospital Amsterdam, The Netherlands E: [EMAIL PROTECTED] T: +31-20-5124737 ______________________________________________________________ This message has been scanned for all viruses by BTnet VirusScreen. The service is delivered in partnership with MessageLabs. This service does not scan any password protected or encrypted attachments. If you are interested in finding out more about the service, please visit our website at http://www.btignite.com/internetservices/btnet/products_virusscreen.htm ============================================================== Season’s Greetings from your friends at Shire! As part of our ongoing commitment to Corporate Responsibility and environmental awareness, it is a Shire tradition not to send cards at this time of the year. The funds that would be used to create and send these cards are contributed to charitable organizations around the globe in regions where Shire employees live and work. Please visit our Shire Corporate Responsibility website (www.shirecr.com) where you can find out more information about the charities we have contributed to this season, under ‘Latest News’. Here’s wishing you a very Merry Christmas, Happy Holiday and peaceful New Year! Please consider the environment before printing this e-mail This email and any files transmitted with it are confidential and may be legally privileged and are intended solely for the use of the individual or entity to whom they are addressed. If you are not the intended recipient please note that any disclosure, distribution, or copying of this email is strictly prohibited and may be unlawful. If received in error, please delete this email and any attachments and confirm this to the sender. www.shire.com