Re: [NMusers] Prednisone and Prednisolone PPK
Dear all, I am working on modelling prednisone and prednisolone PPK in humans given a PO dose of prednisone. Note that prednisone is converted to prednisolone during the first-pass and prednisolone is converted back to prednisone (reversible metabolism). I used a simple 2-cmt PK model (see the code below) that seems to work. However, the model does not appear to be stable and sensitive to initial estimates . Is there an issue of identifiability in this model? does anyone has already worked on PPK of this drug? Furthermore, I would like to model the inhibition of conversion of prednisone to prednisolone as function of time and test drug concentration. Any leads much appreciated. Regards, - Chandra -- $INPUT C ID TIME DV AMT CMT EVID MDV $DATA pred2.CSV IGNORE=C $SUBROUTINES ADVAN8 TRANS1 TOL=5 $MODEL NPAR=7 NCOMP=3 COMP=(DEPOT,DEFDOSE) COMP=(PARENT) COMP=(METAB) $PK KA=THETA(1)*EXP(ETA(1)) VP=THETA(2)*EXP(ETA(2)) CLP=THETA(3)*EXP(ETA(3)) VMT=THETA(4)*EXP(ETA(4)) KF=THETA(5)*EXP(ETA(5)) KB=THETA(6)*EXP(ETA(6)) CLM=THETA(7)*EXP(ETA(7)) S2=VP S3=VMT $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-KF*A(2)+KB*A(3)-CLP*A(2)/VP DADT(3)=KF*A(2)-KB*A(3)-CLM*A(3)/VMT $ERROR FLAG=0 IF(AMT.NE.0) FLAG=1 IPRED=LOG(F+FLAG) R1=0 IF (CMT.EQ.2) R1=1 R2=0 IF (CMT.EQ.3) R2=1 Y2=IPRED+ERR(1) Y3=IPRED+ERR(2) Y=R1*Y2+R2*Y3 IRES=EXP(DV)-EXP(IPRED) $THETA ... $OMEGA ... $SIGMA ... $EST SIG=5 METHOD=1 PRINT=1 MAX= POSTHOC NOABORT
[NMusers] Sparse (pediatric) and rich (adult) data
Hi, I am working on a pop PK model to estimate PK parameters in pediatric and adult patients. Pediatric study (n=20, age 6 yrs) has fewer samples (3) per subject whereas the adult study (n=50, median age 20 yrs) has 12 samples per subject. A two-compartment model best describes the data for each data set. Although a two-compartment model best describes the combined data, the individual parameter estimates in pediatric population are different compared to those obtained using with pediatric data alone. Note that the parameter estimates in adults were not significantly altered with either combined or adult data alone. Body weight is the only covariate included in the model with allometric exponents fixed to 0.75 on CL and 1 on V1. I would like to hear your thoughts on this and any suggestions on how to proceed with modeling combined data from pediatric and adult studies. Regards, - Chandra
Re: [NMusers] Sparse (pediatric) and rich (adult) data
Thank you Nick and Leonid for your comments. Follow-up question: I do understand that 3 samples per subject may not support 4 parameters model. However, historically, the compound showed bi-phasic characteristics (in adults) and I do like to use the same model in pediatrics. Also, the model (ADVAN3, TRANS4) did converge with no issues/errors (with pediatric data alone). Is there something I am missing? or is TRANS5 (AOB, ALPHA, BETA) an alternative for such limited data? Regards, - Chandra Nick Holford [EMAIL PROTECTED] 5/28/2008 1:38:07 PM Chandra, With such a small sample its hard to learn much about differences between adults and children. Your principled approach using allometric scaling is a reasonable way to bridge the gap in recognizing that adults and children are all the same species (see reference below). Children are just small adults I would not be too worried about individual parameter estimate in children being different. With only 3 samples per child and a 2 cmt model requiring at least 4 parameters you will always get different results if you use different assumptions. Nick Anderson BJ, Holford NH. Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32. Chandrasekhar Udata wrote: Hi, I am working on a pop PK model to estimate PK parameters in pediatric and adult patients. Pediatric study (n=20, age 6 yrs) has fewer samples (3) per subject whereas the adult study (n=50, median age 20 yrs) has 12 samples per subject. A two-compartment model best describes the data for each data set. Although a two-compartment model best describes the combined data, the individual parameter estimates in pediatric population are different compared to those obtained using with pediatric data alone. Note that the parameter estimates in adults were not significantly altered with either combined or adult data alone. Body weight is the only covariate included in the model with allometric exponents fixed to 0.75 on CL and 1 on V1. I would like to hear your thoughts on this and any suggestions on how to proceed with modeling combined data from pediatric and adult studies. Regards, - Chandra -- Nick Holford, Dept Pharmacology Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090 www.health.auckland.ac.nz/pharmacology/staff/nholford
