ERROR: ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL

From: David Foster - david.foster@adelaide.edu.au Subject: [NMusers] ERROR: ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL Date: 12/23/2003 1:21 AM Hello all, I seem to be having a few problems with coding/modeling steady-state PK data. Briefly, the subjects are at steady-state with 48 hourly inter-dosing interval, they come in about 47.5 hours (T=47.5) after the previous dose (T=0) and a blood gets taken. Then at 48 hours, they take the "study" dose (same dose/formulation etc as their usual medication) and an intensive blood sampling schedule follows over the subsequent 48 hours (T=48-96 hr). The data are (surprisingly) nice looking, and clearly 2 compartment and it looks like a lag might be there in many subjects. I have about 20 subjects, with about 15 bloods per subject (see below). It runs okay, but when I try to incorporate a LAG, then I get early terminations with error messages that say: PK PARAMETER FOR ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL Considering my initial estimate is 0.25 hours, and II=48, I find this hard to believe... I have tried constraining ALAG1 to <2 hours, but I still get terminations like this: 0PRED EXIT CODE = 1 0INDIVIDUAL NO. 2 ID=0.20000000E+01 (WITHIN-INDIVIDUAL) DATA REC NO. 1 THETA= 3.93E-01 5.02E+01 4.04E+01 4.01E+02 2.01E+01 1.86E-01 OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA PK PARAMETER FOR ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE I NTERVAL 0ITERATION NO.: 5 OBJECTIVE VALUE: 0.2712E+04 NO. OF FUNC. EVALS.:35 CUMULATIVE NO. OF FUNC. EVALS.: 132 PARAMETER: 0.9915E-01 0.1002E+00 0.1005E+00 0.1001E+00 0.9998E-01 0.8578E -01 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1002E+00 GRADIENT: 0.1056E+07 -0.3596E+05 -0.4356E+07 0.1374E+08 -0.2798E+05 0.4382E +06 -0.8636E+03 -0.1988E+04 -0.1510E+04 -0.4564E+04 -0.5046E+04 -0.1614E+04 -0.1934E+06 THETA: KA CL V2 V3 Q ALAG ETA: ERR: CCV XXXXX.lst 2712.412 eval=132 sig=. sub=17 obs=252 CCIL=YNYN NV1.1 PIV1.1 THETA = 0.393 50.2 40.4 401 20 0.186 ETASD = 0.3 0.3 0.3 0.3 0.3 0.3 ERRSD = 0.0500999 MINIMIZATION TERMINATED DUE TO PROXIMITY OF NEXT ITERATION EST. TO A VALUE AT WHICH THE OBJ. FUNC. IS INFINITE AT THE LAST COMPUTED INFINITE VALUE OF THE OBJ. FUNCT.: PRED EXIT CODE = 1 INDIVIDUAL NO. 2 ID=0.20000000E+01 (WITHIN-INDIVIDUAL) DATA REC NO. 1 THETA= 3.93E-01 5.02E+01 4.04E+01 4.01E+02 2.00E+01 1.86E-01 PK PARAMETER FOR ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE IN TERVAL Any suggestions? Thnaks, David I have coded the data as follows: # Example.dat # SS with 2 dose data # ID,AMT,TIME,SS,II,RATE,DV,MDV 1,99705,0.00,1,48,0,.,1 1,.,47.75,.,.,.,42.56,0 1,99705,48.00,0,.,0,.,1, 1,.,48.25,.,.,.,61.87,0 1,.,48.50,.,.,.,133.04,0 1,.,49.00,.,.,.,254.87,0 1,.,49.58,.,.,.,236.67,0 1,.,50.17,.,.,.,237.82,0 1,.,50.58,.,.,.,246.74,0 1,.,51.25,.,.,.,184.27,0 1,.,52.25,.,.,.,169.88,0 1,.,54.25,.,.,.,152.63,0 1,.,57.08,.,.,.,124.84,0 1,.,60.00,.,.,.,104.2,0 1,.,72.08,.,.,.,57.83,0 1,.,83.83,.,.,.,55.07,0 1,.,94.83,.,.,.,52.4,0 The control stream looks like this: $PROBLEM Example control stream $INPUT ID,AMT,TIME,SS,II,RATE,DV,MDV $DATA Example.dat $SUBROUTINES ADVAN4 SS=SS4 TRANS4 $PK KA = THETA(1)*EXP(ETA(1)) CL = THETA(2)*EXP(ETA(2)) V2 = THETA(3)*EXP(ETA(3)) V3 = THETA(4)*EXP(ETA(4)) Q = THETA(5)*EXP(ETA(5)) ALAG1 = THETA(6)*EXP(ETA(6)) K = CL/V2 K23 = Q/V2 K32 = Q/V3 S2 = V2 S3 = V3 $THETA (0,0.4,) ; KA $THETA (0,50,) ; CL $THETA (0,40,) ; V2 $THETA (0,400,) ; V3 $THETA (0,20,) ; Q $THETA (0,0.25,) ; ALAG $OMEGA 0.09 0.09 0.09 0.09 0.09 0.09 $ERROR ;CCV ERROR DEL=0 IF (F.EQ.0) DEL=1 IPRED=F IRES=DV-IPRED IWRES=IRES/(F+DEL) Y = F*(1+ERR(1)) $SIGMA (0.0025) ;CCV ERR(1) $ESTIMATION MAXEVALS=9000 METHOD=1 INTERACTION POSTHOC NOABORT SIG=3 $COVARIANCE PRINT=E $SCATTER DV VS PRED UNIT $SCATTER WRES VS PRED $TABLE ID,AMT,TIME,DV,KA, CL, V2, V3, Q, IPRED,IRES,IWRES NOPRINT ONEHEADER FILE=Example.fit -- David Foster, PhD NHMRC Research Officer Department of Clinical and Experimental Pharmacology Faculty of Health Sciences The University of Adelaide Adelaide, South Australia 5005 Tel: +61 08 8303 5985 Fax: +61 08 8224 0685 Email: david.foster@adelaide.edu.au http://www.adelaide.edu.au/Pharm/index.htm