Multiple dose analysis using NONMEM

From: "Vipul Gupta" vipul686@gmail.com Subject: [NMusers] Multiple dose analysis using NONMEM Date: Mon, 10 Jul 2006 00:40:55 -0400 Hi All, I am trying to analyze a multiple dose oral PK data using NONMEM. The drug is given on 12 h dosing interval for over 30-40 weeks. There are 10-12 sampling points available in first 24 h and then one peak and one trough sample is available until the last dose. Following last dose, 10-12 data points are available for next 24 h. A comparison of first and last dose PK profile indicates a one compartment model with decrease in Cl. The drug is known to cause auto inhibition of its metabolism over time. Data is available only for the parent drug and no information on F is available. My question is : I am not aware of how the changing clearance with time can be modelled using NONMEM ? Any inputs will be appreciated. Thank you Sincerely, Vipul Kumar Post Doc Fellow Department of Pharmaceutics Univ of Florida, Gainesville.

From: "Anthe Zandvliet" Apaza@slz.nl Subject: RE: [NMusers] Multiple dose analysis using NONMEM Date: Mon, 10 Jul 2006 10:37:52 +0200 Dear Vipul, Please take a look at the references below. Iphosphamide and cyclophosphamide autoinduction have been modeled using an enzyme turnover model. In these models, the elimination of the hypothetical enzyme is decreased during exposure to iphosphamide or cyclophosphamide. In order to model autoinhibition, you may consider using this model with a decreased input of the enzyme during drug exposure. Various effect functions are possible (e.g. iphosphamide: Emax, cyclophosphamide:on/off). Anthe references: Kerbusch T, Huitema ADR, Ouwerkerk J, et al: Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM. Br J Clin Pharmacol 49:555-561, 2000 de Jonge ME, Huitema ADR, Rodenhuis S, et al: Integrated Population Pharmacokinetic Model of both cyclophosphamide and thiotepa suggesting a mutual drug-drug interaction. J Pharmacokinet Pharmacodyn 31:135-156, 2004 Anthe Zandvliet Slotervaart Hospital Dept. Pharmacy and Pharmacology Louwesweg 6 1066 EC AMSTERDAM The Netherlands Telephone +31 20 512 4657 FAX + 31 20 512 4753

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

From: tgordi@buffalo.edu Subject: Re: [NMusers] Multiple dose analysis using NONMEM Date: Tue, 11 Jul 2006 20:02:56 -0400 Dear Vipul, I would like to suggest a look at the following paper: Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M.: A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br J Clin Pharmacol. 2005 Feb;59(2):189-98 where we modeled the autoinduction of artemisinin using saliva samples, allowing drug liver amounts to increase the production rate of an enzyme precursor compartment. Enzyme amounts were then correlated directly to the CLin, which using a well-stirred model, resulted in increased extraction degree (EH) of the compound. EH was then related to both total CL and F. The model can be applied to other conditions, such as autoinhibition or changes in f due to displacement. The model performed satisfactorily when applied to another set of limited saliva data (Gordi T, Xie R, Jusko WJ. Br J Clin Pharmacol. 2005 Dec;60(6):594-604) and has done very well in describing the autoinduction of artemisinin in plasma samples from 6 previous studies (manuscript under way). Toufigh Gordi _______________________________________________________