Multiple dose types

TODO Multiple types of doses

As an alternative to using EVID, CMT and RATE to specify infusion doses, one can encode such information in $PK block. Consider

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 $PROBLEM  NETILMICIN
 $INPUT    ID MDV TIME AMT RATE CP=DV KG LENG SEX
           GAGE AGE AGE1 IMIV CREA TAD
 $DATA     data (6F7.0/7X,9F7.0)
 $SUBROUTINE ADVAN3,TRANS4
 $PK
   TVCL1=THETA(1)*KG
   GAGEN=GAGE/39.0
   PAN=(AGE+1.0)/7.0
   IF(GAGE.LT.39.0) THEN
   TVCL=TVCL1*(GAGEN**THETA(3))*(PAN**THETA(2))
   ELSE
   TVCL=TVCL1*(PAN**THETA(2))
   ENDIF
   CL=TVCL*EXP(ETA(1))
   TVV1=THETA(4)*KG
   V1=TVV1*EXP(ETA(2))
   Q=THETA(5)
   V2=THETA(6)*KG
   S1=V1
   IF(IMIV.GE.1.0) THEN
   D1=.0333333   ; 2./60.
   ELSE
   D1=THETA(7)
   ENDIF
 $ERROR
  Y=F*(1+EPS(1))
 $THETA (0,0.07) (0,0.1) (0,1.1) (0,0.4) (0,0.07) (0,0.8) (0,.033)
 $OMEGA 0.02 0.02
 $SIGMA 0.02
 $ESTIMATION PRINT=5 MSFO=msfo1
 $COVARIANCE
 $TABLE MDV ID KG LENG SEX GAGE AGE TAD BY MDV ID NOPRINT FILE=NTABLE.DAT
 $SCATTER PRED VS CP  UNIT

The data items are

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 TIME   hours
 KG     bodyweight(kg)
 LENG   length(cm)
 SEX    0 for female and 1 for male
 GAGE   gestational age at birth
 AGE    actual age (in days)
 AGE1   age at start of therapy
 IMIV   im or iv dose (1.0 is iv and 0.0 is im)
 CREA   creatinine value
 TAD    time after last dose (h)

In particular, IMIV is the flag for two types of doses, intravenous (IV) and intramuscular (IM).

Data snippet (for one subject) below. The subject received both IM and IV doses.

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     6.0    1.0    0.0   13.0   -2.0
     6.0  2.590   47.0    0.0   36.0    0.0    0.0    1.0   56.0           0.0
     6.0    1.0   24.0   10.4   -2.0
     6.0  2.590   47.0    0.0   36.0    1.0    0.0    1.0   56.0           0.0
     6.0    0.0   26.0    0.0    0.0   6.95
     6.0  2.590   47.0    0.0   36.0    1.0    0.0    1.0   56.0    2.0    0.0
     6.0    0.0   32.0    0.0    0.0   3.45
     6.0  2.590   47.0    0.0   36.0    1.0    0.0    1.0   56.0    8.0    0.0
     6.0    0.0   40.0    0.0    0.0    1.8
     6.0  2.590   47.0    0.0   36.0    2.0    0.0    1.0   56.0   16.0    0.0
     6.0    1.0   48.0   10.4   -2.0
     6.0  2.590   47.0    0.0   36.0    2.0    0.0    0.0   56.0           0.0
     6.0    1.0   72.0   10.4   -2.0
     6.0  2.590   47.0    0.0   36.0    3.0    0.0    0.0   56.0           0.0
     6.0    1.0   96.0   10.4   -2.0
     6.0  2.590   47.0    0.0   36.0    4.0    0.0    0.0   56.0           0.0
     6.0    1.0  120.0   10.4   -2.0
     6.0  2.590   47.0    0.0   36.0    5.0    0.0    0.0   56.0           0.0
     6.0    0.0  122.0    0.0    0.0    5.9
     6.0  2.590   47.0    0.0   36.0    5.0    0.0    0.0   56.0    2.0    0.0
     6.0    0.0  128.0    0.0    0.0    2.1
     6.0  2.590   47.0    0.0   36.0    5.0    0.0    0.0   56.0    8.0    0.0
     6.0    0.0  136.0    0.0    0.0   0.75
     6.0  2.590   47.0    0.0   36.0    6.0    0.0    0.0   56.0   16.0    0.0

This example is based on work described in Fattinger K. et al., Netilmicin in the neonate-population pharmacokinetic analysis and dosing recommendations, Clinical Pharmacology and Therapeutics, 1991, Jul, V50; N1:55-65. It illustrates a data file with multiple doses of different kinds.

A FORTRAN format statement is needed to describe the data file because each data record spans two FORTRAN records and also because blanks are sometimes used for null data items.

All doses are given as zero order infusions. The RATE data item is -2, indicating that duration D1 is modeled in the $PK block. There are two types of doses: IV (intravenous) and IM (intramuscular). The duration of IV doses is 2 minutes. The duration of IM doses is unknown and is given by theta(7).

The Estimation Step produces a Model Specification File, which may be used in in a later run; (See $msfi, model specification file).