Intra-species PK scaling from adults to infants for antibody drugs

Hi Nick, Some delayed comments. First is about a trivial comment on the allometry theory. Personally I don't think the allometry has gained sufficient theoretical support. West's model (referene 8) based on the fractal network to prove the 3/4 law is still controversial, which involves both mathematical and statistical aspects. The observational data to support the power law is also insufficient; the 2/3 or 3/4 value is still uncertain for the metabolic rate acorss species, for example. Some allometry (if it is defined as the study of body size and its consquence) phenomenon is a statistical illusion as illustrated in Nee's paper, Science 309, 1236 (2005); here I am not arguing the allometry phenomenon does not exist, what I am trying is that the allometry law should not be fixed at certain values (0.75 for metabolic rate etc, 1 for volume based parameter, etc). The variability is more obvious in our PK area, where the compounds vary with much greater uncertainty in the exponents. Further from the above argument, I don't see strong evidence that we need to fix an exponent at certain value. In the context of modeling, body weight is also a covariate in the model, same as age etc; a THETA estimation for weight should be as feasible as that for age. Of course, by this there would be additional parameters to the model. But sometimes,the model could turn out to give an exponent that is very different from 0.75, then it may be the value in doing this. I agree that it is not a good idea to "scale" Ka between adult and infants. The general observation of smaller Ka (or longer MRT of absorption) in large species (so higher weight) should not be extended without enough evidence to that between infant and adult. Thanks Huadong >>> Nick Holford <[EMAIL PROTECTED]> 2/2/2007 3:47 PM >>> Hi, I think that this discussion needs to take care not to mix up the predictions of allometry with other factors (e.g. adults vs children). Allometric theory (see refs 9 and 10 below) is concerned with how biological properties can be predicted when weights are different. Note that implicitly this means that all other factors are considered to be identical. Allometric theory does not attempt to explain differences which arise from other factors eg. age, organ failure, species, drug interactions, etc. Work done in children and adults has applied allometric theory to predict pharmacokinetic differences attributable to weight alone and then has sought to explain the remaining differences in terms of age (e.g. see refs 1-8 below). The age influences on clearance and volume can be interpreted as being due to developmental maturation. They are quite separate from the changes predicted from allometric scaling. I suggest you take a look at some of the papers which demonstrate how allometric theory and empirical age models can be combined. It is not a good idea to try to estimate an allometric exponent from typical PK data because 1) there is already a good theoretical prediction for the correct value 2) estimation bias for the exponent is difficult to evaluate because of small sample sizes and often narrow weight ranges plus confounding factors such as age. I dont think it is a good idea to expect allometric scaling to explain variability in first-order absorption rate constants. Absorption rates are determined strongly by the physical properties of the drug and the development of absorption processes in infants. I find it hard to imagine how the theory of allometry can be used to predict drug absorption rate constants when weights change. Nick 1. Anderson BJ, Allegaert K, Van den Anker JN, Cossey V, Holford NH. Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol. 2006 Jul 21. 2. Anderson BJ, Allegaert K, Holford NH. Population clinical pharmacology of children: modelling covariate effects. Eur J Pediatr. 2006 Dec;165(12):819-29. 3. Allegaert K, Anderson BJ, Cossey V, Holford NH. Limited predictability of amikacin clearance in extreme premature neonates at birth. Br J Clin Pharmacol. 2006 Jan;61(1):39-48. 4. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth. 2004 Feb;92(2):208-17. 5. van der Marel CD, Anderson BJ, van Lingen RA, Holford NH, Pluim MA, Jansman FG, et al. Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol. 2003 Jul;59(3):243-51. 6. Anderson BJ, Holford NHG. Allometric size modelling for diclofenac and metabolite pharmacokinetic interpretation in children. Australasian Society for Clinical and Experimental Pharmacology and Toxicology; 2003; Sydney, Australia; 2003. 7. Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NHG. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology. 2002;96(6):1336-45. 8. Anderson BJ, McKee AD, Holford NHG. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet. 1997;33(5):313-27. 9. West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997;276:122-26. 10. West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science. 1999;284(5420):1677-9. > > > > > It is an interesting topic. The followings are only some thoughts. > > FcRn is a receptor that was named by "Fc receptor of neonate" discovered > first in mice species. So it is reasonable to > expect that in human infant population as well. But pls do some search on if > studies have been done in human species. > On the other hand, the IgG level in infants would be much lower than that in > adults, therefore, the FcRn mediated > protective mechanism would be expected to be relatively stronger in infants. > As a result, the CL for the exogenous Ab > may not follow the general allometric "rule" of exponent at 0.75 across > infant and adults. Let the population model do the > estimation of the exponent. The individual plotting any logBW vs logCL is > subject to high risk of obtaining abnormal > exponents, esp when the errors in the CL (or AUC) measurement is large. > > About Ka, if the general allometric "rule" (i really don't want to call it a > rule) of exponent for frist-order rate constants > holds at -0.25, you would expect Ka in infant is higher than that in adults - > just an explanation to your observation. > > Hope this helps. > > Huadong Tang > > Drug Safety and Metabolism-Pharmacokinetics > Wyeth Research > Pearl River, NY 10923 > > > >>> "Zhao, Liang" <[EMAIL PROTECTED]> 2/2/2007 10:14 AM >>> > Joe, > > "Another possible approach would be to look at AUCs of raw data, calculate CL > and plot log CL vs log wt and see > what slope, therefore weight exponent, to use in your modelling, as it is > likely that CL will vary with an exponent of wt. " > It is hard to calculate AUC of neonate or infant due to the low number of > allowance for blood samplings (e.g., 2 sampling point > with 4 weeks apart) and previous trials were not designed in a way that adopt > heterogenous sampling schedules and usually > bloods were sampled very rigidly (e.g, at hours 48 and 720). So the Data is > "strictly" sparse even for NONMEM. > > "Or you could just estimate a THETA for an exponent of wt on CL. I suppose > your aim is to delineate size from > maturational processes which will affect CL" > That is a good suggestion. I might have a base model with high ETA's on CL > rather than go ahead estimate THETA. Plot > those ETA's or individual CL's against covairates like weight, BSA, and > gestational age might give some hint. > > Jeroen, > Thank you for hint. It make me realize that it is a very gray area. > One thing I did find is that the absorption rate (Ka) seems to be higher in > infant than adult. That is, if I fix Ka, obtained from > adult data (IM administration), to infant data, the model undersestimated the > conc's for those who were evaluated several > hours earlier than the first nominal time, and the IPRE or PRED went up after > and were good for those who were evaluated > after the first nominal time. Given the physiology composition of infant, I > will assume that is a reasonable assumption. > I will update my findings with you to see the normal allometric WT**0.75 > principle will hold (Inspired by Dr. Nick Holford, since > he will nominate me for Nobel Prize if I find something different ...) > > Regards, > > Liang > > >