$PROBLEM 101, Full TMDD model with 2 binding sites and estimated alpha

$INPUT C=DROP,ID,TIME,AMT,DV,EVID,MDV,CMT,DOSE,TYPE,RATE

$DATA SimulatedData.csv IGNORE = C

$SUBROUTINES ADVAN13 TOL=9

$MODEL

NCOMP=6

$PK

CL = THETA(1)*EXP(ETA(1))

V1 = THETA(2)*EXP(ETA(2))

Q = THETA(3)*EXP(ETA(3))

V2 = THETA(4)*EXP(ETA(4))

K10 = CL/V1

K12 = Q/V1

K21 = Q/V2

F1 = THETA(5)

KA = THETA(6)*EXP(ETA(5))

KON = THETA(7)

KOFF = THETA(8)

KINT = THETA(9)* EXP(ETA(6))

KSYN = THETA(10)*EXP(ETA(7))

KDEG = THETA(11)*EXP(ETA(8))

ALPH = THETA(12)

BASE = KSYN/KDEG

KD = KOFF/KON

KIB = KINT/KON

KSS = KD+KIB

A_0(4) = BASE

$DES

RC =A(5)

R2C=A(6)

CTOT = A(2)/V1

RCTOT= R2C+RC

C = CTOT-RCTOT

RTOT = A(4)

RPTOT= 2*R2C+RC

R = RTOT-RPTOT

; Total Drug depot: amount

DADT(1) =-KA*A(1)

; Total Drug central: amount

DADT(2) = KA*A(1)-K10*C*V1-KINT*RCTOT*V1-K12*C*V1+K21*A(3)

; Free Drug second compartment: amount

DADT(3) = K12*C*V1-K21*A(3)

; Total target central compartment: concentration

DADT(4) = KSYN - KDEG*R - KINT*RPTOT

; Drug-Target Complex RC: concentration

DADT(5) = 2*KON*C*R - (KOFF+KINT+KON*R*ALPH)*RC +2*KOFF*R2C

; Drug-Target Complex R2C concentration

DADT(6) = KON*ALPH*RC*R - (2*KOFF+KINT)*R2C

$ERROR

RRC = A(5)

RR2C= A(6)

CCTOT = A(2)/V1

RRCTOT = RR2C+RRC

CC = CCTOT-RRCTOT

RRTOT = A(4)

RRPTOT = 2*RR2C+RRC

RR = RRTOT-RRPTOT

Y = CCTOT*EXP(EPS(1))

IF(TYPE.EQ.2) Y = RRTOT*EXP(EPS(2))

$THETA

(0,0.3) ; 1 CL

(0,3.00) ; 2 V1

(0,0.2) ; 3 Q

(0,3.0) ; 4 V2

(0,0.7) ; 5 F1

(0,0.5) ; 6 KA

(0,20) ; 7 KON

(0,2) ; 8 KOFF

(0,1) ; 9 KINT

(0,10) ;10 KSYN

(0,10) ;11 KDEG

(0,1) ;12 APLH

$OMEGA

0 FIX ;1 CL

0 FIX ;2 V1

0 FIX ;3 Q

0 FIX ;4 V2

0 FIX ;5 KA

0 FIX ;6 KINT

0 FIX ;7 KSYN

;8 KDEG

$SIGMA

0.01

0.01

$EST METHOD=1 INTERACTION PRINT=10 NOABORT