Re: Scaling for pediatric study planning

Leonid / Joachim, I think we're pushing the envelope on empiricism here. Two facts of reality prevail here: 1) we seldom collect enough data during the absorption phase to assess any meaningful age/developmental dependencies across the age continuum. The fisrt-order assumption is always bad even in adults but we live with it because we seldom have absorption as a primary phase of interest. 2) a physiologic approach, in addition to a more fundamental approximation of reality also has more options with respect to functional expressions that can accomodate developmental factors such as changes in pH dependency, the surface area of the GI tract, or the site and expression of presystemic P450 enzymes all of which factor into the size surrogacy issue. Hence, I'm not sure that I would consider the allometric characterization of absorption in the same manner as one would treat CL or V considerations as it is indeed a hybrid process. I will defer to Nick's wisdom on this but if I am pressed for a guess, I would not scale but pursue more physiologic expressions. In actuality, this is a place where "bottom-up" approaches would seem to have a decided advantage. Jeff Jeffrey S. Barrett, Ph.D., FCP Research Associate Professor, Pediatrics Director, Pediatric Pharmacology Research Unit, Laboratory for Applied PK/PD Clinical Pharmacology & Therapeutics Abramson Research Center, Rm 916H The Children's Hospital of Philadelphia 3615 Civic Center Blvd. Philadelphia, PA 19104 KMAS (Kinetic Modeling & Simulation) Institute for Translational Medicine University of Pennsylvania email: [EMAIL PROTECTED] Ph: (267) 426-5479 >>> Leonid Gibiansky <[EMAIL PROTECTED]> 9/19/2008 11:20 AM >>> Just to add: c) how do we allometrically scale a VM rate constant of the Michaelis-Menten elimination model: C1=A(1)/V1 DADT(1)= ... -A(1)*VM/(KM+C1) d) do we need to allometrically scale a KM constant of the Michaelis-Menten elimination model ? any experience with these quantities (for example, if they were estimated, what were the estimates, with the precision)? My suggestion would be NOT to scale a), b) and d), and scale VM as the rate constant (~ WT**(-0.25)) but I do not have "rock-solid" data to support those suggestions. Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 [EMAIL PROTECTED] wrote: > > Dear NM_Users, > > we have all been good students and listened to Nick when he told us > again and again the rock-solid truths of allometry: > > Volume: *(WT/70) > > CL: *(WT/70)**0.75 > > any rate constant related to distribution or elimination: *(WT/70)**(-0.25) > > Here my questions: > a) how do we allometrically scale a first-order rate constant of > absorption after oral dosing? > > b) how do we allometrically scale a first-order rate constant of > absorption from a subcutaneous injection site? > > Thank you for your thoughts, > > Joachim > > __________________________________________ > Joachim GREVEL, Ph.D. > MERCK SERONO International S.A. > Exploratory Medicine > 1202 Geneva > Tel: +41.22.414.4751 > Fax: +41.22.414.3059 > Email: [EMAIL PROTECTED] > > ------------------------------------------------------------------------ > > This message and any attachment are confidential, may be privileged or > otherwise protected from disclosure and are intended only for use by the > addressee(s) named herein. If you are not the intended recipient, you > must not copy this message or attachment or disclose the contents to any > other person. If you have received this transmission in error, please > notify the sender immediately and delete the message and any attachment > from your system.