Weight normailized doses in modeling

From: "TKT (Thomas Klitgaard Tygesen)" <tkt@novonordisk.com> Subject: [NMusers] Weight normailized doses in modeling Date: Fri, 26 Oct 2001 22:19:24 +0200 Dear nmusers: Could some of you enlighten me with some considerations on dose normalizations (by weight) in PK/PD modeling? I'm in the process of setting up a dose dependant one-compartment model on insulin and have all my dose in weigh normalized units. Moreover, I have a number of covariates which I'd like to investigate, as to their influence on model parameters (by looking at the eta's and the individual parameters estimates, plotted against these covariates). However, it may be that my model should be expressed in absolute doses (e.g. by multiplying a dose of, say, 0.3 U/kg by each subjects weight) before running the estimation. Otherwise, my final parameters will in some way be expressed in per kg units. Does the per kg estimation present any particular problems (e.g. by masking covariate effect) or is more a matter of practice? Thanks in advance. Thomas K Tygesen Civil engineer Direct +45 44424960 Fax +45 44421940 tkt@novonordisk.com

From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: [NMusers] Weight normailized doses in modeling Date: Mon, 29 Oct 2001 19:23:37 +1300 Thomas, The key issue here is what is "normal" about weight normalised units? Tradition (but not necessarily reason) has decided that doses/kg are "normal". But the relationship between key pharmacokinetic parameters such as clearance and half-life is not linearly related to weight. My advice is to use the actual dose and scale the model parameters using allometric science rather than flat earth tradition. See these references for the theory and application: Anderson BJ, Holford NHG. Aspects of theophylline clearance in children. Anaesth Intens Care 1997;25:497-501. Anderson BJ, McKee D, Holford NHG. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clinical Pharmacokinetics 1997;33:313-327. Anderson BJ, Woolard G, Holford NHG. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children. Br J Clin Pharmacol 2000;50:125-134. West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997;276:122-26. West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999;284(5420):1677-9. Nick -- Nick Holford, Divn Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556 http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm

From: jlukas@usal.es Subject: Re: [NMusers] Weight normailized doses in modeling Date: Mon, 29 Oct 2001 11:28:54 MET Hello Thomas, Your model (1 comp PK) has no way of "knowing" the units of the object you are giving it as dose=AMT, so the parameters will not be scaled per kg. On the contrary, the magnitude of your AMT entry in nonmem may be incorrect with respect to your concentrations (which I assume are not scaled per kg) so the parameters may simply come out wrong. You could obtain scaled per kg parameters by setting e.g. TVCLW=THETA(1)*WT etc. within the model (and then maybe having to account for this in the S1 scales depending on what the units of your dose finally are and whether you also scaled V). In terms of how you actually introduce the AMT item, if you now have it in mg/kg for example then use S1=V/WT to scale for WT, if your concentrations are not already scaled. In any case, obviously, the units of the your modeled and observed concentrations must match. Apart from the references that Nick suggests you may also want to look at the theophylline problem in the nonmem manuals. I hope this helps! Cheers, John Lu kas Dept of Pharmacy University of Salamanca Spain + 34 647545633