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From: <j.h.proost_at_rug.nl>

Date: Wed, 6 Dec 2017 20:02:12 +0100

Dear Rob,

A few comments to your message: In a PharmPK thread in 2013, cited by

you, Nick Holford explained his approach for using estimates of GFR for

dose adjustment, in answer to a message from myself, suggesting an

approach suggested long time ago by Dettli and others. This can be

written as:

CL_renal_drug = fr * eGFR

where CL_renal_drug is the renal clearance of the drug (in ml/min), fr

is the (dimensionless) ratio of renal clearance of the drug (assumed to

be drug-specific, but independent of GFR), eGFR is the estimated value

for GFR (irrespective of the method, expressed in ml/min, not

ml/min/1.73m2).

As far as I know, there is no literature comparing both approaches, so

it remains to be determined which approach is 'best'.

You are completely right that it may be questioned whether this holds

for drugs that are actively secreted. For the latter, an additional

clerance term may be added, using allometric scaling with exponent 0.75.

The CKD-EPI equation does not contain any measure of body size. This is

not really surprising, since GFR is expressed in ml/min/1.73m2. This

value is scaled for body surface area, which is rather close to

allometric scaling with a factor of 0.75. The eGFR expressed in ml/min,

which is an estimate of the actual GFR, is affected by weight and

height, as expected.

Note that eGFR expressed in ml/min/1.73m2 is used by nephrologists as a

measure of renal function, but for estimation of renal clearance and

dosing purposes, one should always use eGFR in ml/min. For example, the

Dettli approach can be used for any estimate of eGFR, provided that

values in ml/min/1.73m2 are converted to ml/min, using the body surface

area estimated from weight and height.

best regards,

Johannes H. Proost

Department of Pharmacokinetics, Toxicology and Targeting

University of Groningen

the Netherlands

Op 5-12-2017 om 18:17 schreef R.terHeine_at_radboudumc.nl:

*>
*

*> 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.
*

*>
*

Received on Wed Dec 06 2017 - 14:02:12 EST

Date: Wed, 6 Dec 2017 20:02:12 +0100

Dear Rob,

A few comments to your message: In a PharmPK thread in 2013, cited by

you, Nick Holford explained his approach for using estimates of GFR for

dose adjustment, in answer to a message from myself, suggesting an

approach suggested long time ago by Dettli and others. This can be

written as:

CL_renal_drug = fr * eGFR

where CL_renal_drug is the renal clearance of the drug (in ml/min), fr

is the (dimensionless) ratio of renal clearance of the drug (assumed to

be drug-specific, but independent of GFR), eGFR is the estimated value

for GFR (irrespective of the method, expressed in ml/min, not

ml/min/1.73m2).

As far as I know, there is no literature comparing both approaches, so

it remains to be determined which approach is 'best'.

You are completely right that it may be questioned whether this holds

for drugs that are actively secreted. For the latter, an additional

clerance term may be added, using allometric scaling with exponent 0.75.

The CKD-EPI equation does not contain any measure of body size. This is

not really surprising, since GFR is expressed in ml/min/1.73m2. This

value is scaled for body surface area, which is rather close to

allometric scaling with a factor of 0.75. The eGFR expressed in ml/min,

which is an estimate of the actual GFR, is affected by weight and

height, as expected.

Note that eGFR expressed in ml/min/1.73m2 is used by nephrologists as a

measure of renal function, but for estimation of renal clearance and

dosing purposes, one should always use eGFR in ml/min. For example, the

Dettli approach can be used for any estimate of eGFR, provided that

values in ml/min/1.73m2 are converted to ml/min, using the body surface

area estimated from weight and height.

best regards,

Johannes H. Proost

Department of Pharmacokinetics, Toxicology and Targeting

University of Groningen

the Netherlands

Op 5-12-2017 om 18:17 schreef R.terHeine_at_radboudumc.nl:

Received on Wed Dec 06 2017 - 14:02:12 EST