Hoem, N.O. and Jelliffe, R
School of Pharmacy, University of Oslo, Norway, and the Laboratory of Applied Pharmacokinetics, USC School of Medicine, Los Angeles, CA
Ciclosporine – A (CYA) is, despite being one of the drugs. most widely subjected to therapeutic drug monitoring, still a difficult substance to model. This is particularly so when the drug is taken per os, presenting a very steep and narrow absorption and distribution peek, totally dominating the early part of a typical 12 hour dosing interval. Several processes, both intestinal and hepatic, underlie this complex absorption. We specifically focused on the P-glycoprotein (PgP) dependent transport back into the gut, and modeled CYA absorption as a time dependent process. Initially a high, non-saturated back transport capacity is reflected in a low speed of absorption. Absorption then increases gradually as the PgP pathway becomes saturated. We modeled absorption with a cumulative Weibull function. Flux from the absorptive compartment was described as:
where T = time after dose; X1 = mass of drug in absorptive compartment; Ka = absorption constant, and A and B are the Weibull constants. This function is a flexible sigmoid multiplier of fa. It can describe a saturable absorptive process and time and also a time lag. This function was implemented in an NPEM analysis of populations of subjects given ciclosporine. It captured ciclosporine pharmacokinetics well, including absorption, peak-concentration and distribution profile. The Weibull function is a useful method for describing time dependent and/or saturable absorption and lag time.
Supported by NIH Grant RR11526
Reference: PAGE 10 (2001) Abstr 244 [www.page-meeting.org/?abstract=244]
Poster: poster