Rich data set

From: "David Nix, Pharm D." <nix@pharmacy.arizona.edu> Subject: Rich data set Date: Mon, 14 May 2001 10:12:59 -0700 I am trying to fit some data involving administration of a drug under four different conditions. The individual data exhibit good fits using a one-compartment model with first order absorption and first order elimination, except that a lag time is necessary in most cases. The data consists of 16 subjects each being administered 4 different treatments. There are 15 samples available per subject. I deleted all "0" concentrations at the end of each profile, and some of the 0 concentrations between the dose and first detectable concentration. I am having two problems: 1. the lag time is not handled very well. An estimate for lag time was 98.9 hours for the run using the control steam below. If I set an upper bound, the estimate approaches this bound. 2. Errors NO. OF SIG. DIGITS IN FINAL EST.: 3.1 (sometimes unreportable), R MATRIX ALGORITHMICALLY SINGULAR, COVARIANCE MATRIX UNOBTAINABLE, S MATRIX ALGORITHMICALLY SINGULAR. I have tried many things to get around these problems including using different residual error models, etc. I have included at least one "0.0" concentration in the data at the time prior to the first measurable concentration following the dose. The control stream follows: $PROBLEM POPULATION DATA $INPUT ID PERD TX SEQ DOSE=AMT TIME DV AGE SEX RACE SMOK $INPUT HT WT BMI LBW CLCR $DATA LOFAZ2.PRN $SUBROUTINES ADVAN2 TRANS2 $PK TVKA=THETA(1) TVCL=THETA(2) TVV=THETA(3) KA=TVKA*EXP(ETA(1)) CL=TVCL*EXP(ETA(2)) V=TVV*EXP(ETA(3)) S2=V ALAG1=THETA(4)*EXP(ETA(4)) >>>IF(TX.EQ.1) TVLAG=2.34 >>>IF(TX.EQ.2) TVLAG=1.67 >>>IF(TX.EQ.3) TVLAG=2.14 >>>IF(TX.EQ.4) TVLAG=2.43 ; I have tried fixing the lag time given the best estimates of the mean from individual estimates. ; ALAG1=TVLAG*EXP(ETA(4)) $ERROR DEL=0 IF(F.EQ.0) DEL=1 IPRED=F W=(F**2+THETA(5)**2)**0.5 W=W+DEL IRES=DV-IPRED IWRES=IRES/W PHI2=1 IF(TX.EQ.2) PHI2=THETA(6) PHI3=1 IF(TX.EQ.3) PHI3=THETA(7) PHI4=1 IF(TX.EQ.4) PHI4=THETA(8) Y=(IPRED+W*EPS(1))*PHI2*PHI3*PHI4 ; PHI2 is the relative bioavailability of treatment 2 compared to treatment 1 ; PHI3 is the relative bioavailability of treatment 3 compared to treatment 1 ; PHI4 is the relative bioavailability of treatment 4 compared to treatment 1 ; All treatments involve administration of the same drug and dose; however, Tx1 is fasting, Tx2 is ; with food, Tx3 is w/acidic juice and Tx4 is w/ antacid $THETA (0,1.0) (0,202) (0,1270) (0,2) (0,0.05) $THETA (0,1.5) (0,1) (0,.94) $OMEGA 0.25 0.25 0.25 0.25 $ESTIMATION METHOD=0 POSTHOC MAXEVAL=1000 NOABORT $COVR Any suggestions on revised coding or troubleshooting would be greatly appreciated.