RE: [NMusers] Additive model for IOV and IIV within a logit-transform

Dear Mahesh,
 
The relevant parts of the code we used was the following
 
IV=0

IF (FORM.EQ.5) IV=1

CR=0

IF (FORM.EQ.2.OR.FORM.EQ.7) CR=1

IR=0

IF (FORM.EQ.1.OR.FORM.EQ.6) IR=1

OCCF=IOV*(OCC1*ETA(7)+OCC2*ETA(8)+OCC3*ETA(9)+OCC4*ETA(10)); IOV
FDIR=1+((1-IV)*IR*THETA(16)*(DOS-10000)/1000); centered at middle dose

FDCR=1+((1-IV)*(1-IR)*THETA(17)*(DOS-30000)/1000) ; dose-effect =
centered at middle dose
FGEN=1+(THETA(22)*PM)+THETA(27)*HET ; CYP2D6 effect

 

;immediate release

TF1 =FGEN*FDIR*THETA(10)

PHI =LOG(TF1/(1-TF1))

TVF1=EXP(PHI+ETA(5)+OCCF)/(1+EXP(PHI+ETA(5)+OCCF))

; cont. release

IF (FORM.EQ.7) THEN

   TF1 =FGEN*FDCR*THETA(11)

   PHI =LOG(TF1/(1-TF1)) ;F CR

   TVF1=EXP(PHI+ETA(6)+OCCF)/(1+EXP(PHI+ETA(6)+OCCF))

ENDIF

You can see that both the IIV (ETA(6)) and IOV (OCCF) are inside the =
logit-transform. The dose effect (FDCR) of a continuous release =
formulation (CR) was centered at the middle dose of 30mg. So indeed the =
reported typical value for F is different for each dose, but the IIV and =
IOV are independent of dose. A different typical F was estimated for =
immediate release formulations and also with a different IIV (but not =
IOV, was not supported as separate for IR/CR).

Friendly regards,

Thomas

Thomas Kerbusch, PhD
Section Head PK-PD
Dept. CPK
N.V. Organon - XW 3133
PO Box 20
5340 BH Oss
The Netherlands
tel: +31 412 661621
cell: +31 613045046 (intern 4936)
fax: +31 412 662542
Thomas.Kerbusch_at_organon.com

 

  _____

From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] =
On Behalf Of Samtani, Mahesh [PRDUS]
Sent: Saturday, 30 June, 2007 1:12
To: nmusers_at_globomaxnm.com
Subject: [NMusers] Additive model for IOV and IIV within a =
logit-transform



Dear NMusers,
In a paper by Kerbusch, Wählby, Milligan, & Karlsson (BJCP 56 (6), =
639-652) the authors state that: "The bioavailability (F) depended on =
the formulation (immediate = IR or extended = CR), the dose, and =
CYP2D6 genotype. Interindividual variation for FIR and FCR, and =
interoccasion variability for FIR and FCR were described using additive =
models within a logit-transform" and reported

VARIABILITY ESTIMATE (CV)
IIV F,IR 67% (20%)
IIV F,CR 67% (20%)
IOV F 37% (13%)

Could a kind NMuser please provide the additive model for IOV and IIV =
within a logit-transform. MORE importantly, please elucidate the formula =
for computing the variability estimate of IIV and IOV in F. The table =
footer states "F: bioavailability centred at median dose". Does this =
mean that the reported variability estimate is only relevant at the =
computed F value for the median dose?

Thanking you in advance...MNS



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Received on Mon Jul 02 2007 - 06:12:44 EDT