RE: [NMusers] Allometric scaling of renal clearance with estimated glomerular filtration rate

From: STANDING, Joseph (GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS FOUNDATION TRU <joseph.standing_at_nhs.net>
Date: Sun, 10 Dec 2017 22:25:09 +0000

Dear Nick,

I was trying to point out that using a model, in this case a model for GFR,=
 to predict the value of a covariate in a PK model may not be necessary. I=
 don't know if it would be worse than unnecessary e.g. cause bias, since co=
variates enter the model assumed to be measured without error.

Regarding your comment on local fit not implying generalisability, in one o=
f the examples I cited, Dr Henning's tobramycin model, was built with data =
on 732 patients and 5,605 PK samples! Ideally I suppose one would want to =
prove generalisability by prdicting external data however, so here is an ex=
ample of using SECR and allometric/age scaling (no redress to model-predict=
ed covariates) which beat 11 other published models at predicting a prospec=
tively collected external dataset representing the population we were inter=
ested in:

Germovsek E et al. Development and Evaluation of a Gentamicin Pharmacokinet=
ic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitor=
ing in Neonates and Infants. Antimicrob Agents Chemother. 2016 Jul 22;60(8)=
:4869-77.

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: Nick Holford [n.holford_at_auckland.ac.nz]
Sent: 07 December 2017 20:58
To: STANDING, Joseph (GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS FOUNDAT=
ION TRUST); R.terHeine_at_radboudumc.nl; nmusers_at_globomaxnm.com
Cc: max.taubert_at_uk-koeln.de; ruben.faelens_at_gmail.com; j.h.proost_at_rug.nl
Subject: Re: [NMusers] Allometric scaling of renal clearance with estimated=
 glomerular filtration rate

Dear Joe,

On 08-Dec-17 02:00, STANDING, Joseph (GREAT ORMOND STREET HOSPITAL FOR CHIL=
DREN NHS FOUNDATION TRUST) wrote:

Dear Rob,

Why do you want to use a model to predict the value of a covariate to add i=
nto your model? Apart from glomerular filtration rate, what other situatio=
ns would you do this?

I'm not sure what you are trying to say here. What model for GFR are you th=
inking 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 clea=
rance,

Unless you want to assume that the drug is completely eliminated renally th=
en there should always be a "fancy separation" of renal and non-renal clear=
ance. I don't know of any clear cut case where I could assume a drug can on=
ly be eliminated by the kidneys.

I would simply ignore the fact there is a model to predict glomerular fltra=
tion, 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/me=
dian 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 empirici=
sm 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 wi=
thout cystic fibrosis. Clin Pharmacokinet. 2013 Apr;52(4):289-301

Cystatin C example:
De Cock PA. Augmented renal clearance implies a need for increased amoxici=
llin-clavulanic acid dosing in critically ill children. Antimicrob Agents C=
hemother. 2015 Nov;59(11):7027-35.

Just because a model can provide a local fit to the data does not mean it h=
as good properties for generalization / extrapolation. Incorporating biolog=
ical mechanism and sensible extrapolation properties should be used wheneve=
r 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: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ow=
ner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com>] on behalf =
of R.terHeine_at_radboudumc.nl<mailto:R.terHeine_at_radboudumc.nl> [R.terHeine_at_ra=
dboudumc.nl<mailto:R.terHeine_at_radboudumc.nl>]
Sent: 07 December 2017 11:56
To: nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>
Cc: n.holford_at_auckland.ac.nz<mailto:n.holford_at_auckland.ac.nz>; max.taubert@=
uk-koeln.de<mailto:max.taubert_at_uk-koeln.de>; ruben.faelens_at_gmail.com<mailto=
:ruben.faelens_at_gmail.com>; j.h.proost_at_rug.nl<mailto:j.h.proost_at_rug.nl>
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 filt=
ration 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, whe=
n compared to the Cockroft-Gault. In general, sample sizes of pharmacokinet=
ic 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 th=
is is likely a poor body size descriptor to scale renal function.

Also, depending on the population and drug one may choose one equation abov=
e another. For example: if a drug is completely filtrated (no active secret=
ion), a cystatin C based equation is likely better explain variability in c=
learance 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 cre=
atinine-independent equations may provide better equations.

Thinking about this the last couple of days and with your feedback, I am in=
clined to choose the equation based on population (e.g. cachectic or not?) =
and drug (e.g. filtration/active secretion) and, if the equation scales ren=
al 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: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [mai=
lto:owner-nmusers_at_globomaxnm.com] Namens Nick Holford
Verzonden: woensdag 6 december 2017 20:06
Aan: nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>
Onderwerp: Re: [FORGED] [NMusers] Allometric scaling of renal clearance wit=
h estimated glomerular filtration rate

Hi Rob,

Thanks for bringing this up again. I don't think much has changed since I w=
rote 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 forglomerul=
ar filtration rate has no theoretical nor experimental support when compare=
d to theory based allometry (Rhodin et al. 2009). So I donot agree with sta=
ndardizing CLCR to 1.73 m^2. I know this is frequently done but in fact thi=
s is just based on tradition and an out of datetheory of scaling based on s=
urface area (see Anderson & Holford 2008)."

There is no biological or experimental support for using surface area to sc=
ale renal function markers such as GFR and CLcr. In contrast, there is str=
ong 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 a=
bsurdity 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 ser=
um creatiniine. This is based on the definition of clearance and is true wi=
thout any assumptions.
CLcr=CER/Scr
If we then assume Scr is at steady state then CER will be equal to creatini=
ne production rate (CPR) and we can use this:
CLcr=CPR/Scr
All rational models for predicting CLcr without measurement of CER use mode=
ls to predict CPR e.g.

CPR=(140-Age)*Weight/72 use Cockcroft & Gault to predict CPR in males th=
en CLcr=CPR/Scr is Cockcroft & Gault CLcr ml/min

Dividing CPR by Scr gives the CLcr. This can be written equivalently but le=
ss clearly:
CLcr=CPR*Scr^-1

The empirical models such as MDRD and CKI-EPI (see below) involve the absur=
dity of estimating the known exponent for Scr of -1. These estimates must b=
e wrong based on the theory I have outlined above (unless the estimate is e=
xactly -1). The reported estimates are -1.209 for CKI-EPI and -1.154 for MD=
RD.

In addition, and more importantly,they have no direct measure of body size =
which seriously limits the value outside the typical weight distribution an=
d they are only applicable to adults. GFR can be described from premature n=
eonates to adults using theory based allometry and maturation based on post=
-menstrual age so GFR predicttions should try to follow the concepts used t=
here (Rhodin 2008).

So what to do?

First -- don't use MDRD or CKI-EPI unless you are sure you are applying the=
m to a population similar to that used to develop these empirical predictio=
ns. You could add allometric scaling to the eGFR by assuming the 1.72m^2 va=
lue 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 th=
en the Matthews (2004) equation for adults. I am working on an integrated m=
ethod 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 0.9=
93^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 (standa=
rdized 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, R.terHeine_at_radboudumc.nl<mailto:R.terHeine_at_radboudumc.n=
l> 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, Im also interested whether other people have considered
allometric scaling of MDRD/CKD-EPI derived GFRs?

Cheers,

Rob

*Van: *Ruben Faelens <ruben.faelens_at_gmail.com><mailto:ruben.faelens_at_gmail.c=
om>
*Datum: *dinsdag 5 december 2017 om 7:13 PM
*Aan: *"Heine, Rob ter" <R.terHeine_at_radboudumc.nl><mailto:R.terHeine_at_radbou=
dumc.nl>
*CC: *"nmusers_at_globomaxnm.com"<mailto:nmusers_at_globomaxnm.com> <nmusers_at_glob=
omaxnm.com><mailto:nmusers_at_globomaxnm.com>
*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><https://academic.o=
up.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, R.terHeine_at_radboudumc.nl<mailto:R.terHeine_at_radboudumc.n=
l> 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:n.holford_at_auckland.ac.nz<mailto:email:n.holford_at_auckland.ac.nz>
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 hande=
lsregister onder nummer 41055629.
The Radboud university medical center is listed in the Commercial Register =
of the Chamber of Commerce under file number 41055629.


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--
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: n.holford_at_auckland.ac.nz<mailto:n.holford_at_auckland.ac.nz>
http://holford.fmhs.auckland.ac.nz/
http://orcid.org/0000-0002-4031-2514
Read the question, answer the question, attempt all questions



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Received on Sun Dec 10 2017 - 17:25:09 EST

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