NONMEM Users Network Archive

Hosted by Cognigen

Posting to nmusers

From: Kimberly Kimshim <pharmsuni>
Date: Thu, 27 Feb 2014 18:03:34 +0900

Hello. This is Kim who needs to complete my thesis with regards to
population pharmacokinetics.
I collected drug A concentration data from outpatient records. Since it was
collected retrospectively, it was consisted of trough levels and had huge
variation in this dataset by visual checking.

Therefore, I fixed the Ka since I did not have much information to explain
absorption part. I estimated Ka and Vd only to find poor estimation of Vd
and then, I fixed Vd to reference value (without eta value) and added
covariates to both Ka and Vd to estimate covariate effects.

$PK
T1 = THETA(1)
T2 = THETA(2)
T3 = THETA(3)

TVCL=T1
TVV=T2
TVKA=T3

CL = TVCL *EXP(ETA(1))
V = TVV
KA = TVKA

S2=V/1000
K=CL/V


$ERROR
IPRED=F
W=IPRED+0.0001
IRES=IPRED-DV
IWRE = IRES/W
Y= IPRED + W*EPS(1)

$THETA
(28.8) ;
(454) ;
(4.5) FIX ;

$OMEGA
 0.351

$SIGMA
 0.275


I started with nineteen covariates and seventeen of them were related to Ka
and/or Vd in Full model. Final model is as follows;

TVCL=THETA1*EXP(THETA5*(SCRR-1.12))

TVV=THETA2*EXP(THETA4*(SCRR-1.12))*EXP(THETA6*(ALBU-3.82))

The final model looked okay and clinical correlation of each covariate to
Ka and Vd made senses to me. However, my advisor wants to fix the Vd but
consider body weight of each individuals. The problem is that only half of
the subjects had their body weights known. Base model showed huge~~~ Eta
value in clearance (2.0E+021%). Eta value in Vd was 68.5%.

$PK
T1 = THETA(1)
T2 = THETA(2)
T3 = THETA(3)
T4 = THETA(4)

TVCL=T1
TVV=T2*(BWTT/64.1+0.001)
TVKA=T3

CL = TVCL *EXP(ETA(1))
V = TVV *EXP(ETA(2))
KA = TVKA

S2=V/1000*(BWTT/64.1+0.001)
K=CL/V

$ERROR
IPRED = F
IRES = DV - IPRED
W = THETA(4)
WRES = IRES/W
Y = IPRED+W*EPS(1)

$THETA
(5.51) ;
(159) ;
(4.5) FIX ;
(3.36) ;

$OMEGA
 120
 0.327

$SIGMA
 1 FIX

My question is which is the best way to establish base model for this
dataset (trough only)? Fixing Vd with covariate effect consideration (fixed
effect model?) Fixing Vd without estimation? Fixing Vd adaptive to body
weight?

Thank you for your reply in advance.

- Kim



--
***********************************************
Mi Kyong Kim Shim, Pharm.D., RPH,
Researcher, MS candidate in clinical pharmacy.
School of Pharmacy
Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul, South Korea 151-742
TEL. 82-2-2072-0335
FAX 82-2-766-9560
E-mail pharmsuni

Received on Thu Feb 27 2014 - 04:03:34 EST

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to: nmusers-request@iconplc.com.

Once subscribed, you may contribute to the discussion by emailing: nmusers@globomaxnm.com.