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] _____ 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 This message, including attachments, is confidential and may be privileged. If you are not an intended recipient, please notify the sender then delete and destroy the original message and all copies. You should not copy, forward and/or disclose this message, in whole or in part, without permission of the sender.
