Autoinduction model - An increased clearance(day 1- 14)
Dear All,
I am working on a Pop PK data where the patients are treated with HIV drug.
An autoinduction is involved with prolonged administration of the drug. An
increased CL is expected from day 1 to day 14.
We have intense data on day 1 and day 14 with sparse data between. Since a
lag period is involved for the induction I used the equation *CL* = *
CLinduced* -(*CLinduced - CLpre)*exp*(-*kout*(t*-*Tlag*)) described by Johan
Gabrielsson as more appropriate.
Also when I included a lag period for absorption in my earlier model my fits
are better and OBF decreased by 200.
However the final model with or without lag time for absorption + auto
induction model is either terminated or covariance step is being aborted.
I changed the initial estimates several times but still no luck. Though the
Auto induction model aborts the fits are better than the lag time model
however the estimates for Vd are 4 fold less than the expected.
I appreciate your input and suggestions. Here is my code.
$SUBROUTINES ADVAN13 TRANS1 TOL=5 ;(I used ADVAN6 too)
$MODEL
NPAR=9 NCOMP=4
COMP=(DEPOT,DEFDOSE)
COMP=(LAG)
COMP=(OBSV,DEFOBS)
COMP=(PERIP)
$PK
CLP=THETA(1)
CLI=THETA(6)
KOUT=THETA(7)
TLAG=THETA(8)*EXP(ETA(6))
TVCL=CLI-(CLI-CLP)*EXP(-KOUT*(TIME-TLAG))
CL=TVCL*EXP(ETA(1))
TVV2=THETA(2)
V2=TVV2*EXP(ETA(2))
TVQ=THETA(3)
Q=TVQ*EXP(ETA(3))
TVV3=THETA(4)
V3=TVV3*EXP(ETA(4))
TVKA=THETA(5)
KA=TVKA*EXP(ETA(5))
TVALAG1=THETA(9)
ALAG1=TVALAG1*EXP(ETA(7))
S3=V2
$DES
K=CL/V2
K23=Q/V2
K32=Q/V3
DADT(1)=-KA*A(1)
DADT(2)=KA*A(1)-A(2)/ALAG1
DADT(3)=A(2)/ALAG1-K23*A(3)-K*A(3)+K32*A(4)
DADT(4)=K23*A(3)-K32*A(4)
$ERROR
DEL=0
IF (F.LE.0.0001) DEL=1
IPRE=F
W1= 1
W2= F
IRES= DV-IPRE
IWRE=IRES/(W1+W2)
Y = F + W1*ERR(1) + W2*ERR(2)
DV2=ABS(V2-TVV2)
$EST METHOD=1 INTERACTION PRINT=5 MAX=9999 SIG=3 MSFO=JLM.MSF
$THETA
(0, 6);[CLP]
(0, 90);[V2]
(0, 19);[Q]
(0, 200);[V3]
(0, 0.16);[KA]
(0, 8);[CLI]
(0, 0.001);[KOUT]
(0, 250);[TLAG]
(0, 0.3);[ALAG1]
$OMEGA
0.23 ;[CL] omega(1,1)
0.18;[V2] omega(2,2)
0 FIXED ;[Q] omega(3,3)
0.42;[V3] omega(4,4)
0.19;[KA] omega(5,5)
0.09;[TLAG for Ka]
0.1;[ALAG1 for CLI]
$SIGMA
0.06 ;[P] sigma(1,1)
0.09 ;[A] sigma(2,2)
$COV MATRIX=S
Regards,
Shankar Lanke Ph.D.
University at Buffalo
Office # 716-645-4853
Fax # 716-645-2886
Cell # 678-232-3567