Re: Allometric scaling of renal clearance with estimated glomerular filtration rate

On 08-Dec-17 02:00, STANDING, Joseph (GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS FOUNDATION TRUST) wrote: > Dear Rob, > > Why do you want to use a model to predict the value of a covariate to add into > your model? Apart from glomerular filtration rate, what other situations would > you do this? I'm not sure what you are trying to say here. What model for GFR are you thinking about as the only example? I could mention using a model for FFM based on covariates of WT, HT and SEX as an example but I don't know if this is what you mean. > Unless I was trying to do some fancy separation of renal and non-renal > clearance, Unless you want to assume that the drug is completely eliminated renally then there should always be a "fancy separation" of renal and non-renal clearance. I don't know of any clear cut case where I could assume a drug can only be eliminated by the kidneys. > I would simply ignore the fact there is a model to predict glomerular > fltration, and include its component parts e.g. > > CL = THETA * (WT/70)**0.75 * FCREAT * FAGE > > where FCREAT and FAGE are covariate functions for creatinine (e.g. (SECR/median > value)**THETA ) and age. No explicit assumption of the pathway of elimination but just an empirical functions of SCR. This can include the bizarre MDRD and CKD-EPI functions which include skin colour as a covariate. I consider this kind of empiricism when there are mechanistic alternatives to be bad science. > Some examples of not using a model to predict GFR still gave an acceptable > model of CL (what we were interested in): > > Creatinie e.g. > Hennig S. Population pharmacokinetics of tobramycin in patients with and > without cystic fibrosis. Clin Pharmacokinet. 2013 Apr;52(4):289-301 > > Cystatin C example: > De Cock PA. Augmented renal clearance implies a need for increased > amoxicillin-clavulanic acid dosing in critically ill children. Antimicrob > Agents Chemother. 2015 Nov;59(11):7027-35. Just because a model can provide a local fit to the data does not mean it has good properties for generalization / extrapolation. Incorporating biological mechanism and sensible extrapolation properties should be used whenever possible. Best wishes, Nick > BW, > > Joe > > Joseph F Standing > MRC Fellow, UCL Institute of Child Health > Antimicrobial Pharmacist, Great Ormond Street Hospital > Honorary Senior Lecturer, St George's University of London > Tel: +44(0)207 905 2370 > Mobile: +44(0)7970 572435 > ________________________________________ > From: [email protected] [[email protected]] on behalf of > [email protected] [[email protected]] > Sent: 07 December 2017 11:56 > To: [email protected] > Cc: [email protected]; [email protected]; [email protected]; > [email protected] > Subject: RE: [NMusers] Allometric scaling of renal clearance with estimated > glomerular filtration rate > > Dear Nick, Hans, Ruben, Max, > > Great to hear several approaches and opinions on the use of glomerular > filtration approximations in PK modeling and scaling to body size. Thank you! > > I have a hard time ignoring the CKD-EPI equations (with or without cystatin C), > as they are well established and proven better predictors for GFR, when > compared to the Cockroft-Gault. In general, sample sizes of pharmacokinetic > studies are smaller than those where the CKD-EPI and MDRD equations were > developed. I am not convinced that developing a new creatinine/cystatin c > equation for GFR for each PK analysis is the right approach. Then again, I also > have a hard time scaling to BSA, as in, for example, obese patients this is > likely a poor body size descriptor to scale renal function. > > Also, depending on the population and drug one may choose one equation above > another. For example: if a drug is completely filtrated (no active secretion), > a cystatin C based equation is likely better explain variability in clearance > of completely filtrated drugs (e.g. carboplatin). Another example: in cachectic > patients one may argue that there is not enough muscle mass (and thus serum > creatinine) to provide accurate GFR estimations and then creatinine-independent > equations may provide better equations. > > Thinking about this the last couple of days and with your feedback, I am > inclined to choose the equation based on population (e.g. cachectic or not?) > and drug (e.g. filtration/active secretion) and, if the equation scales renal > function to BSA, convert it to scaling to FFM. Nonetheless, open to any other > suggestion or discuss cons and pro's anytime! > > Sincerely, > Rob > > -----Oorspronkelijk bericht----- > Van: [email protected] [mailto:[email protected]] Namens > Nick Holford > Verzonden: woensdag 6 december 2017 20:06 > Aan: [email protected] > Onderwerp: Re: [FORGED] [NMusers] Allometric scaling of renal clearance with > estimated glomerular filtration rate > > Hi Rob, > > Thanks for bringing this up again. I don't think much has changed since I wrote > this in 2013 > ( http://cognigencorp.com/nonmem/current/2013-August/4697.html) > > 1. Theory Based Allometry or Surface Area > > "Note that using surface area as a form of size standardization forglomerular filtration > rate has no theoretical nor experimental support when compared to theory based allometry > (Rhodin et al. 2009). So I donot agree with standardizing CLCR to 1.73 m^2. I know this is > frequently done but in fact this is just based on tradition and an out of datetheory of > scaling based on surface area (see Anderson & Holford 2008)." > > There is no biological or experimental support for using surface area to scale > renal function markers such as GFR and CLcr. In contrast, there is strong > biological based theory and experimental support for using theory based allometry > (see Holford & Anderson 2017 for a recent review). > > 2. Mechanism Based Models for CLcr > > I also wrote in 2013: > > "The MDRD method of predicting glomerular filtration rate is astatistical absurdity > which does not include any measurement of size for its prediction. I would certainly not > recommend using it for anyscientific purpose." > > This applies equally well to the CKD-EPI method. Let me explain why it is a > absurdity generated by a naive statistician using CLcr as an example. > > CLcr can be calculated from the creatinine excretion rate (CER) and the serum > creatiniine. This is based on the definition of clearance and is true without > any assumptions. > CLcr=CER/Scr > If we then assume Scr is at steady state then CER will be equal to creatinine > production rate (CPR) and we can use this: > CLcr=CPR/Scr > All rational models for predicting CLcr without measurement of CER use models > to predict CPR e.g. > > CPR=(140-Age)*Weight/72 use Cockcroft & Gault to predict CPR in males then > CLcr=CPR/Scr is Cockcroft & Gault CLcr ml/min > > Dividing CPR by Scr gives the CLcr. This can be written equivalently but less > clearly: > CLcr=CPR*Scr^-1 > > The empirical models such as MDRD and CKI-EPI (see below) involve the absurdity > of estimating the known exponent for Scr of -1. These estimates must be wrong > based on the theory I have outlined above (unless the estimate is exactly -1). > The reported estimates are -1.209 for CKI-EPI and -1.154 for MDRD. > > In addition, and more importantly,they have no direct measure of body size > which seriously limits the value outside the typical weight distribution and > they are only applicable to adults. GFR can be described from premature > neonates to adults using theory based allometry and maturation based on > post-menstrual age so GFR predicttions should try to follow the concepts used > there (Rhodin 2008). > > So what to do? > > First -- don't use MDRD or CKI-EPI unless you are sure you are applying them to > a population similar to that used to develop these empirical predictions. You > could add allometric scaling to the eGFR by assuming the 1.72m^2 value is > equivalent to 70 kg with a fat free mass (FFM) of > 56.1 kg. Then scaling the eGFR by (WT/70)^(3/4) or (FFM/56.1)^(3/4). > > I use the Schwartz (1992) equations for neonates, children and teenagers then > the Matthews (2004) equation for adults. I am working on an integrated method > for CPR prediction which was presented as a work in progress at PAGE this year. > Watch this space... > > Best wishes, > > Nick > > MDRD > eGFR =175 x (SCr)^-1.154 x (age)-0.203 x 0.742 [if female] x > 1.212 [if Black] > > CKI-EPI > eGFR = 141 x min(SCr/k, 1)^alpha x max(SCr /kappa, 1)^-1.209 x > 0.993^Age x 1.018 [if female] x 1.159 [if Black] > kappa = 0.7 (females) or 0.9 (males) > alpha = -0.329 (females) or -0.411 (males) > > eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2; SCr (standardized > serum creatinine) = mg/dL > > Holford NHG, Anderson BJ. Allometric size: The scientific theory and > extension to normal fat mass. Eur J Pharm Sci. 2017;109(Supplement):S59-S64. > > Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, > Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH > Human renal function maturation – a quantitative description using > weight and postmenstrual age. Pediatr Nephrol. 2008 > > Schwartz GJ. Does kL/PCr estimate GFR, or does GFR determine k? Pediatr > Nephrol. 1992;6(6):512-5. > > Matthews I, Kirkpatrick C, Holford N. Quantitative justification for > target concentration intervention -- parameter variability and > predictive performance using population pharmacokinetic models for > aminoglycosides. Br J Clin Pharmacol. 2004;58(1):8-19. > > Holford N, Sherwin CM. Scaling renal function in neonates and infants to > describe the pharmacodynamics of antibiotic nephrotoxicity. PAGE 26 > Abstr 7208 [wwwpage-meetingorg/?abstract=7208]. 2017. > > On 06-Dec-17 23:52, [email protected] wrote: > > > Hi Ruben, > > > > Interesting work, Ruben. One may indeed question the validity of > > glomerular filtration rate markers like cystatin C (that is only > > filtrated and not actively secreted) to predict PK of drugs that > > undergo active tubular secretion in patients with decreased renal > > function. When glomerular filtration rate drops, the relative > > contribution of active tubular secretion to renal clearance increases. > > To me, it appears logical that creatinine is a better marker for > > clearance drugs that are actively secreted, as creatinine also > > undergoes active tubular secretion. > > > > Nonetheless, I’m also interested whether other people have considered > > allometric scaling of MDRD/CKD-EPI derived GFR’s? > > > > Cheers, > > > > Rob > > > > *Van: *Ruben Faelens <[email protected]> > > *Datum: *dinsdag 5 december 2017 om 7:13 PM > > *Aan: *"Heine, Rob ter" <[email protected]> > > *CC: *"[email protected]" <[email protected]> > > *Onderwerp: *Re: [NMusers] Allometric scaling of renal clearance with > > estimated glomerular filtration rate > > > > Dear Rob, > > > > At PMX Benelux, there was an interesting talk about the correlation > > between different metrics describing renal function by Stijn Jonckheere. > > A part of the work presented was published: > > https://academic.oup.com/jac/article/71/9/2538/1750427 > > https://academic.oup.com/jac/article/71/9/2538/1750427 > > > > This may provide some perspective, or rather complicate things even > > more, depending on your viewpoint. > > > > Best regards > > Ruben Faelens > > On 06-Dec-17 06:17, [email protected] wrote: > > > Dear all, > > > > I am wondering what your thoughts are on the allometric scaling of > > clearance of renally extreted drugs, where we have estimations renal > > function. > > > > Simply scaling the predicted glomerular filtration rate from, for > > example, the Cockroft-gault equation seems inappropriate, since weight > > is already a part of the equation. Standardizing this to weight in the > > Cockroft-gault equation can be done, a solution has been discussed > > here: http://cognigencorp.com/nonmem/current/2013-August/4697.html > > > > However, in the recent years some new equations to calculate > > glomerular filtration rate from endogenous markers have emerged. For > > example the CKD-EPI CREATININE CYSTATIN C equation > > https://www.kidney.org/content/ckd-epi-creatinine-cystatin-equation-2012 > > . As the addition of a muscle mass independent endogenous marker like > > cystatin C is known to provide better estimations of GFR in, for > > example, cachectic patients, it is likely that this equation may > > outperform to predict renally filtrated compounds in this patient > > group. It is rather odd that this CKD-EPI equation does not contain > > any measure of body size. The outcome of this equation is a GFR scaled > > to a BSA of 1.73m^2. > > > > I am wondering how you would allometrically scale the eGFRs from these > > CKD EPI equations to, for example, fat-free mass. > > > > Cheers! > > > > Rob > > > > R. ter Heine, PhD, PharmD > > > > Hospital Pharmacist-Clinical Pharmacologist > > > > Radboudumc, Nijmegen, The Netherlands > > > > Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het > > handelsregister onder nummer 41055629. > > The Radboud university medical center is listed in the Commercial > > Register of the Chamber of Commerce under file number 41055629. > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72 > email:[email protected] > http://holford.fmhs.auckland.ac.nz/ > http://orcid.org/0000-0002-4031-2514 > Read the question, answer the question, attempt all questions > > Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het > handelsregister onder nummer 41055629. > The Radboud university medical center is listed in the Commercial Register of > the Chamber of Commerce under file number 41055629. > > ******************************************************************************************************************** > > This message may contain confidential information. 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NHSmail is approved for exchanging patient data and > other sensitive information with NHSmail and other accredited email services. > > For more information and to find out how you can switch, > https://portal.nhs.net/help/joiningnhsmail -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72 email: [email protected] http://holford.fmhs.auckland.ac.nz/ http://orcid.org/0000-0002-4031-2514 Read the question, answer the question, attempt all questions