Re: [NMusers] Transit compartment model with multiple dose data

[Justin Wilkins]

Dear Fabrice, Since the model is dying with the first individual in the data, one explanation might lie with the initial estimates of your model parameters. A suggestion would be to implement the model in an exploratory modelling tool like Berkeley Madonna to see whether the initial estimates are OK, and the model is behaving as it should. It's worth mentioning as well that this model really needs quite a bit of information in the absorption phase in order to be useful - if data in this region of your PK profiles is limited, you'll almost certainly see numerical issues.  The only obvious issue I see with the implementation in the code you've provided is that F1 (bioavailability of the dose compartment) should be set to 0, since dosing is completely handled by the model code (assuming DOSE is set in $DATA and is appropriately populated in every record in the data file) - if not, you'll want to add IF(AMT.GT.0) DOSE=AMT to your control stream as well. Hope that's helpful! Best Justin On 4/13/11 8:49 AM, fabr...@arlenda.com wrote: Dear NMusers, I am trying to implement the transit compartments absorption model as described by Savic et al. (1). As my dataset includes some multiple dosing data, I have recoded the actual time as time after last dose (see code below), as suggested by Wilkins et al. (2) However, I always got the following error message for the first observation record: 0PROGRAM TERMINATED BY OBJ ERROR IN OBJ2 WITH INDIVIDUAL 1 ID= 1.01010000000000E+04 CONDITIONAL CONTRIBUTION OR IT'S DERIVATIVE IS INFINITE MESSAGE ISSUED FROM ESTIMATION STEP AT INITIAL OBJ. FUNCTION EVALUATION I have tried to play with the initial estimates, but always with the same outcome. The relevant part of the code is given here below. Thanks in advance for any suggestion! Fabrice Fabrice Nollevaux, Pharmacometrician Arlenda SA www.arlenda.com (1) Savic et al. J Pharmacokinet Pharmacodyn (2007) 34:711-726 (2) Wilkins et al. Antimicrob Agents Chemother (2008) 52(6):2138-2148 ... $SUBROUTINES ADVAN6 TOL=3 $MODEL NCOMP=3 COMP(DEPOT, DEFDOSE) ; absorption compartment COMP(CENTRAL,DEFOBS) ; central compartment COMP(PERIPH) ; peripheral compartment $PK KA = THETA(1)*EXP(ETA(1)) CL = THETA(2)*EXP(ETA(2)) V2 = THETA(3)*EXP(ETA(3)) Q = THETA(4)*EXP(ETA(4)) V3 = THETA(5)*EXP(ETA(5)) KTR = THETA(8) N = THETA(9) S2 = V2/1000 K = CL/V2 K23 = Q/V2 K32 = Q/V3 LNFAC = LOG(2.5066)+(N+0.5)*LOG(N)-N IF (AMT.GT.0) TDOS=TIME $DES TALD=T-TDOS ; Time after last dose DADT(1) = EXP(LOG(DOSE)+LOG(KTR)+N*LOG(KTR*TALD)-KTR*TALD-LNFAC)-KA*A(1) DADT(2) = KA*A(1)-K*A(2)-K23*A(2)+K32*A(3) DADT(3) = K23*A(2)-K32*A(3) $ERROR IPRED=F IF (F.GT.0) THEN W=(F*F*THETA(6)**2+THETA(7)**2)**0.5 ELSE W=1 ENDIF Y=F+W*EPS(1) IRES=DV-IPRED IWRES=IRES/W ... -- Justin Wilkins, PhD Exprimo NV Tel: +41 (0) 81 599 23 82 Mobile: +41 (0) 76 561 09 49 E-mail: justin.wilk...@exprimo.com Web: www.exprimo.com This e-mail is confidential. It is also privileged or otherwise protected by work product immunity or other legal rules. The information is intended to be for use of the individual or entity named above. If you are not the intended recipient, please be aware that any disclosure, copying, distribution or use of the contents of this information is prohibited. You should therefore delete this message from your computer system. If you have received the message in error, please notify us by reply e-mail. The integrity and security of this message cannot be guaranteed on the Internet. Thank you for your co-operation.