Re: Multiple dose analysis using NONMEM

From: Justin Wilkins justin.wilkins@farmbio.uu.se Subject: Re: [NMusers] Multiple dose analysis using NONMEM Date: Mon, 10 Jul 2006 13:28:48 +0200 Dear Anthe & Vipul, The original question related to autoinhibition rather than autoinduction, I guess, but an enzyme turnover model could still be adapted to work in the way suggested. One could also consider other semi-mechanistic ways of dealing with the problem as well, such as a competitive interaction model, for example - but I've never seen one in practice. There's another published example of an enzyme turnover model in Hassan M, Svensson US, 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. Br J Clin Pharmacol. 1999 Nov;48(5):669-77. Here, amount of drug in the central compartment increases the rate of production of enzyme in the enzyme compartment (rather than its rate of elimination) while the amount of enzyme in the enzyme compartment, in turn, increases clearance of the drug from the central compartment. This seems, to me, to be more mechanistically appropriate than the approaches mentioned earlier. Justin -- Justin Wilkins, PhD ----------------------------------------------- Division of Pharmacokinetics and Drug Therapy Department of Pharmaceutical Biosciences Uppsala University ----------------------------------------------- P.O. Box 591 SE-751 24 Uppsala Sweden ----------------------------------------------- justin.wilkins@farmbio.uu.se ----------------------------------------------- Work: +46 18 471 4304 Mobile: +46 768 506 606 Fax: +46 18 471 4003 MSN: justin.wilkins@farmbio.uu.se