Re: Coadministered drugs (PK-PD)

From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: Coadministered drugs (PK-PD) Date: Tue, 02 Oct 2001 08:06:57 +1200 Atul, ;Set CMT to 1 for Drug A, 2 for Drug B, 5 for precursor and 6 for effect mediator ;Set AMT and RATE for A and B to define the infusions ;Set AMT=1 and RATE=0 for precursor and effect mediator at TIME=0 to initialize these CMTs $INPUT ID TIME ... CMT AMT RATE ... DV MDV ;Because you want to use an indirect effect model you will need to use PREDPP and one of the DE ADVANs e.g. ADVAN6. $SUBR ADVAN6 TOL=3 ;Set up the model structure: $MODEL COMP (DRUGA1) ; central for A COMP (DRUGA2) ; peripheral for A COMP (DRUGB1) ; central for B COMP (DRUGB2) ; peripheral for B COMP (PRECUR) ; precursor COMP (MEDIAT) ; mediator $PK ;assign parameters V1A=THETA(V1A) ... ; At steady state without drug KIN=KOUT*E0 therefore E0P=KINP/KOUTP F5=E0P ; initial conc (E0P) of effect precursor E0M=E0P*KINM/KOUTM F6=E0M ; initial conc (E0M) of effect mediator $DES C1A=A(1)/V1A C2A=A(2)/V2B C1B=A(3)/V1B C2B=A(4)/V2B C1P=A(5) C1M=A(6) DADT(1)= QA*C2A - (QA+CLA)*C1A DADT(2)= QA*(C1A - C2A) DADT(3)= QB*C2B - (QB+CLB)*C1B DADT(4)= QB*(C1B - C2B) EA=1-C1A/(C50A+C1A) ; PD model for A EB=1+C1B/(C50B+C1B) ; PD model for B ; details of precursor and mediator eqns are up to you to figure out DADT(5)= KINP*EA - KOUTP*C1P ; precursor DADT(6)= C1P*KINP - KOUT*C1E*EB ; Effect mediator $ERROR IF (CMT.EQ.1) THEN CA=A(1)/V1A Y=CA*EXP(ERRA) ENDIF IF (CMT.EQ.3) THEN CB=A(3)/V1B Y=CB*EXP(ERRB) ENDIF IF (CMT.EQ.5) THEN CEP=A(5) Y=CEP + ERRP ENDIF IF (CMT.EQ.6) THEN CEM=A(6) Y=CEM + ERRM ENDIF -- Nick Holford, Divn Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556 http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm