Re: [NMusers] Re: Weight based dosing

From: Michael Fossler <mfossler_at_trevenainc.com>
Date: Wed, 9 Dec 2015 02:50:48 +0000

While it is important to look at the variability explained by the covariate=
, your question is not really a statistical one. You need to evaluate the c=
linical significance of the change in exposure by weight. For a given dose,=
 how does exposure change by weight and how will this affect the efficacy o=
f the antibiotic under various assumptions of bacterial sensitivity? Think =
about how you can use your model to answer the clinical question - you won'=
t find the answer in p-values or objective function changes.

Mike Fossler

On Dec 8, 2015, at 9:28 PM, Sultan,Abdullah S <a3bdu3_at_ufl.edu<mailto:a3bdu3=
_at_ufl.edu>> wrote:


Hi Rudy Gunawan,


Thanks for the helpful information,


I tried both methods, fixing the exponents at 0.75 and 1 and estimating the=
m, results for both models are similar, No other covariate (demographic var=
iables or lab test) showed any correlation with Cl/F.


my main question is how important is it to look at the variability explaine=
d by a covariate? And can it be used to determine if a covrariate is not cl=
inically significant


Thanks,

Abdullah Sultan




________________________________
From: Rudy Gunawan <RGunawan_at_isisph.com<mailto:RGunawan_at_isisph.com>>
Sent: Tuesday, December 8, 2015 8:10 PM
To: Sultan,Abdullah S; nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com=
>
Subject: RE: Weight based dosing


Hi Abdullah Sultan,



Since your estimate is not too far from 0.75 exponent in Clearances, did yo=
u try using the theoretical allometric scaling (0.75 in all clearances and =
1.00 in volumes)? With these, it would be easier to justify. Once you inclu=
de the body size, I would suggest you check the matrix plots of ETA in CL o=
r V versus other covariates (demo, labs, etc) to see if there is any other =
info would help explain the variability. Without knowing more of the nature=
 of the drug, I think these would help build the model.



Hope this helps,



Rudy



From: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ma=
ilto:owner-nmusers_at_globomaxnm.com] On Behalf Of Sultan,Abdullah S
Sent: Tuesday, December 08, 2015 4:40 PM
To: nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>
Subject: [NMusers] Weight based dosing



Hi everyone,



I am developing a POP PK model for an anti-infective drug, I am trying to d=
etermine if dosing should be weight based or not. The range of weight in th=
e study was 40-100 kg.



Weight was statistically significant for Cl/F but only explained 9% of the =
variability observed for Cl.



I used allometric scaling to describe weights effect on Cl/F and slope effe=
ct of weight was 0.58, and scaled to 60 kg (the median).



Based on the slope effect estimated, AUC is predicted to decrease by 15% fo=
r an 80 kg individual, and increase by 25% for an individual that weights 4=
0 kg compared to a 60 kg individual.



How much should I trust the slope effect determined by my study? and should=
 I rely on it to develop the dosing regimen?

if weight only explained 9% of variability observed with Cl/F, could that i=
ndicate that it is not clinically significant and weight based dosing is no=
t required?







Thanks,

Abdullah Sultan, PhD candidate

University of Florida

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Received on Tue Dec 08 2015 - 21:50:48 EST

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