Re: Questions about M3

Xiao Hu, Please see comments inserted within your code examples below. Regards, Luann Phillips Xiao Hu wrote: > Dear NMusers, > > I'm seeking inputs/advice on some M3 related questions. Any comments and suggestions would be appreciated. > > I have some Phase 1 data on a drug, which I want to model with a M3 method. The LLQ is 10 and peak level is about 80 (it's a cytokine and can't ask assay people to do a better job). > > I'm using NONMEM 7, therefore, can use PHI function directly. Below you can see my initial code (Code 1). I first modeled SIG as a separate THETA(5). The estimated THETA(5) turned out to be 1.14E6. Therefore, all the PREDs=0.5 with TYPE==2. I had to admire NONMEM because it makes (LOQ-IPRE)/SIG close to zero and give me a politically golden answer (Prob=0.5) on my LLQ data. > > Since SIG represents the variance of F, in my second try, I set SIG=SD*SD and modeled log-tranformed data, because I'm using exponential model on the ERROR. The code is following the initial code (Code 2). > > Here's my questions. > > 1. Is code 2 a theoretically correct approach? How is SIG generally modeled based on your experience? 2. Currently, I only included one BLQ post Tmax. The rest were ignored (MDV=1). If I include one BLQ timepoint before Tmax, the model won't run. If I include every BLQ time points after Tmax, the model won't run. Is this acceptable? What's the general practice? > > 3. What are the diagnostic tools for BLQ from the M3 method? > > 4. If I model SIG using all the data, and fix it in the subsequent runs, which use the same code as Code 1 with SIG fixed, will this be acceptable? > > Code 1: > $SUBROUTINES ADVAN2 > $PK > MU_1=THETA(1) > MU_2=THETA(2) > MU_3=THETA(3) > MU_4=THETA(4) > SD=MU_4 > KA=EXP(MU_1+ETA(1)) > V=EXP(MU_2+ETA(2)) > CL=EXP(MU_3+ETA(3)) > K=CL/V > S2=V/1000 > $ERROR *******SIG = SD of variance which is defined as SD=MU_4 above ******* so I think you should have SIG=MU_4 or SIG=SD ******* instead of THETA(5) ******* Your code was using a separate estimate of variance for the LOQ concentrations than for the > LOQ concentrations. References show using the same variance for both types. > SIG=THETA(5) > LOQ=10 > IPRE=F > IF(SIG==0) EXIT *****I would move the calculations for DUM and CUMD inside the IF statement for TYPE.EQ.2 to prevent unnecessary calculations. ****DUM = (LOQ-IPRE) / SQRT(Variance) Since you are using a exponential error model which is equivalent to the constant CV error model (Y=F+F*ERR) in NM, the SQRT(variance) would be F*SIG so DUM=(LOQ-IPRE)/(F*SIG) > DUM=(LOQ-IPRE)/SIG > CUMD=PHI(DUM) > IF(TYPE.EQ.1) THEN > F_FLAG=0 > Y= F*EXP(SD*ERR(1)) > ENDIF > IF(TYPE.EQ.2) THEN > F_FLAG=1 > Y=CUMD > ENDIF > $THETA > -1.868;[KA] > 11.9 ;[V] > 10;[CL] > > 0.523;[SD] 0.2 > > $OMEGA > > 0.258 0.177 > > 0.227 > $SIGMA > 1 FIX > > $EST METHOD=COND LAP INTERACTION MAXEVAL=9999 PRINT=5 FILE=PK.M3.COND.ext > > Code 2 > $SUBROUTINES ADVAN2 > $PK > MU_1=THETA(1) > MU_2=THETA(2) > MU_3=THETA(3) > MU_4=THETA(4) > SD=MU_4 > SIG=SD*SD > KA=EXP(MU_1+ETA(1)) > V=EXP(MU_2+ETA(2)) > CL=EXP(MU_3+ETA(3)) > K=CL/V > S2=V/1000; DOSE IN 1000 U, CONC in U, VOLUME IN mL > $ERROR > LOQ=LOG(10) *****IF F=0 then LOG(F)= -Infinity so you probably don't want to change IPRE=LOG(0) to 0. LOG(F)=0 corresponds to F=1. You may want to try IPRE= -10 or -20 instead. > IF(F==0) THEN > IPRE=0 > ELSE > IPRE=LOG(F) > ENDIF > IF(SIG==0) EXIT *****In this case because the error model becomes additive, DUM=(LOQ-IPRE)/SIG is correct. > DUM=(LOQ-IPRE)/SIG > CUMD=PHI(DUM) > IF(TYPE.EQ.1) THEN > F_FLAG=0 > Y= LOG(F)+SD*ERR(1) > ENDIF > IF(TYPE.EQ.2) THEN > F_FLAG=1 > Y=CUMD > ENDIF > $THETA > -1.868;[KA] > 11.9 ;[V] > 10;[CL] > > 0.523;[SD] $OMEGA 0.258 0.177 > > 0.227 > $SIGMA > 1 FIX > $EST METHOD=COND LAP INTERACTION MAXEVAL=9999 PRINT=5 FILE=PK.LOG.COND.ext > > Sample Data for code 1: > Sample Data for code 2: > > Best regards, > > Xiao Hu (Shelley), Ph.D. > Scientist, > Development Pharmacokinetics & Disposition > Biogen Idec, Inc. > 14 Cambridge Center > Cambridge, MA 02142 > Phone: 617-679-3586 > Fax: 617-679-3463