RE: 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
[EMAIL PROTECTED]
_____
Quoted reply history
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Samtani, Mahesh
[PRDUS]
Sent: Saturday, 30 June, 2007 1:12
To: [email protected]
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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