RE: Intra-species PK scaling from adults to infantsfor antibody drugs

>From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On >Behalf Of Huadong Tang >Sent: den 14 februari 2007 19:10 >To: Nick Holford; nmusers >Subject: Re: [NMusers] Intra-species PK scaling from adults to infantsfor >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 >> >> >> >> From: Elassaiss - Schaap, J. (Jeroen) >[mailto:[EMAIL PROTECTED] >> Sent: Friday, February 02, 2007 5:41 AM >> To: Zhao, Liang >> Cc: Joseph Standing >> Subject: RE: [NMusers] Intra-species PK scaling from adults to infants for >antibody drugs >> >> Liang, >> >> Please be careful, as specific capacities may not scale well across age >groups in man (from neonate to elderly). Relative >> metabolic capacities for clearance of small molecules appear to change >markedly, for example. I do not know how that >> translates to antibody kinetics. You may find relevant hits in the >following search: >> > http://scholar.google.nl/scholar?hl=nl&lr=&q=pediatric+pharmacokinetic+antib >ody >> >> best regards, >> Jeroen >> >> J. Elassaiss-Schaap >> Scientist PK/PD >> Organon NV >> PO Box 20, 5340 BH Oss, Netherlands >> Phone: + 31 412 66 9320 >> Fax: + 31 412 66 2506 >> e-mail: [EMAIL PROTECTED] >> >> -----Original Message----- >> From: [EMAIL PROTECTED] >[mailto:[EMAIL PROTECTED] On Behalf Of Joseph >> Standing >> Sent: Friday, 02 February, 2007 10:14 >> To: Zhao, Liang; [email protected] >> Subject: Re: [NMusers] Intra-species PK scaling from adults to >infants for antibody drugs >> >> Liang, >> >> One approach would be to use allometric scaling of wt^0.75 on CL and >just wt on VD. However, this is >> based on observations across species in adult animals of how basal >metabolic rate scales with weight. How >> BMR scales with wt within a species during development has yet to be >investigated to my knowledge >> (please send me references if you know different). >> >> 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. 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, and that is easier said than done! >> >> Can't offer any advice on FcRn recycling as I don't know what it >means, but assume that if it is a clearance >> process then bigger animals will clear the antibody faster, therefore >CL will increase with weight in some >> way. >> >> Joe >> >> >> Joseph F Standing >> Centre for Paediatric Pharmacy Research >> School of Pharmacy/UCL Institute of Child Health >> 29/39 Brunswick Square >> London WC1N 1AX >> >> >> At 18:29 01/02/2007, Zhao, Liang wrote: >> >> Dear all, >> >> Is there any population model/experience available to perform >intra-species PK scaling from adults to infants for >> antibody drugs? >> >> Specifically, how to scale volume of distribution and clearance if >the antibody is eliminated via FcRn recycling route >> (t1/2 = ~20 days). >> >> High appreciation for your inputs! >> >> >> >> Liang Zhao Ph. D. >> >> >> This message, including attachments, is confidential and may be >privileged. If you are not an intended recipient, please >> notify the sender then delete and destroy the original message and all >copies. You should not copy, forward and/or >> disclose this message, in whole or in part, without permission of the >sender. >> >> >> > > > >-- >Nick Holford, Dept Pharmacology & Clinical Pharmacology >University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand >email:[EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:373-7556 > http://www.health.auckland.ac.nz/pharmacology/staff/nholford/