Description of column-types used to define the dose regimen

AMOUNT: dose amount

The content of column AMOUNT will be called the dose-column. It shall either contain a double value or string “.”. When there is no EVID or MDV column, when a dose-column contains a double value different from 0 then it will be considered as a dose-line (i.e. a line containing dose information).

Remarks

  • If there is a non null dose and a value in the response-column, we consider it as both dose and response. Is was formerly considered as a response.
  • In MonolixSuite version prior to 2018R1, in the case of the definition of both a non null amount and a measurement, the choice was made to favor the measurement. It is no longer the case. However, providing two distinct lines to provide both a dose-line and a response line is still possible and recommended.

Format restrictions (an exception will be thrown otherwise):

  • A data set shall not contain more than one column-type AMOUNT.
  • AMOUNT column shall either contain a double value or string “.”.

ADM: Administration type

The goal of this column is to be able to define several types of administration (e.g. oral administration, intravenous,…). The integer in the ADM column works like a flag, which can be used in the model file to link the dose informations of the data set to a specific administration route in the model. For instance, with the following data set:

ID TIME AMT ADM Y
John 0 10 1 .
Eric 0 20 2 .

and the following PK block in the Mlxtran model file:

PK:
iv(type=1)
oral(type=2, ka)

the subject John will receive a dose of 10 via a bolus iv, while subject Eric will receive a dose of 20 orally with first-order rate constant ka. The identifier in the ADM column should match the “type=” field of the macro. We recommend using ADM to define the type of dose only, and set ADM=”.” for response-lines (in this case, the string “.” will not be interpreted as a repetition of the previous column).

Moreover, it is possible to combine the information of the type of response (as YTYPE) in case of response-lines. Thus, if there are several outputs and several administration routes it is possible to set all the information in the ADM column. The several possibilities using YTYPE and ADM are summarized in the following table

Type of line \ Case YTYPE off / ADM off   YTYPE on/ ADM off   YTYPE off / ADM on   YTYPE on/ ADM on
Response line Only one output Defined using YTYPE Defined using ADM      Defined using YTYPE
Dose line Only one administration route (type = 1) Only one administration route (type = 1) Defined using ADM     Defined using ADM

Notice that, for readability and better understanding), we strongly recommend to

  • use ADM to define the type of dose only, and set ADM=”.” for response-lines
  • use YTYPE to define the type of output, and set YTYPE = “.” or the first value for dose lines

Format restrictions (an exception will be thrown otherwise):

  • For dose-lines, the column shall contain only positive integers. For response-lines strings or integers are allowed.
  • A data set shall not contain more than one ADM column-type.

RATE, TINF: rate and infusion duration

These columns enable to define the rate (RATE column-type) or duration (TINF column-type) of doses administered as infusions. The column content is meaningful only for dose-lines. The rate and duration information is transferred to the model via the use of the iv macro. If a RATE is defined, the duration of the infusion will be AMOUNT/RATE. If a TINF is defined, the rate will be AMOUT/TINF.
We strongly recommend to have small duration values (less than 10) to be able to manage it efficiently with analytical solutions. Indeed, if the duration is too long, the calculation of the exponential may produce NaN. Two workarounds:
– Either rescale your time to have durations relevants w.r.t. your time
– If not possible, you may use ODEs and not analytical solutions.

Format restrictions (an exception will be thrown otherwise):

  • A data set shall not contain more than one column with column-type RATE or TINF.
  • “.” or 0 means a bolus dose, without any infusion rate or time.
  • Values can be any double value.
  • If a negative value is used in combination with the iv macro, the administration will be a bolus.

STEADY STATE, INTERDOSE INTERVAL: steady-state and inter-dose interval

Steady-state is used to specify that any transitory effect is over and that the system response is now a periodic function of doses. To do this, a fixed number of doses (by default 5) is added before the dose entered with the STEADY STATE flag set to true (so 6 doses in total, by default). The period between doses is set to the INTERDOSE INTERVAL. The number of doses can be changed in the data frame and will be saved in the project file.

Remark:

  • In version prior MonolixSuite2018R1, the number of added doses can be changed in the preferences.xmlx file, located in <home>/lixoft/monolix/config in the user folder. The number of doses was defined in the line <dosesToAddForSteadyState value="5"/>, and can for instance be changed to <dosesToAddForSteadyState value="20"/>.

On the following example:

ID TIME AMT SS II EVID Y
Tom 0 10 1 2 1 .

5 doses are applied, at times -10, -8, -6, -4, -2 in addition to the dose at time = 0. The above data set is thus equivalent to:

ID TIME AMT SS II EVID Y
Tom -10 10 0 0 1 .
Tom  -8 10 0 0 1 .
Tom  -6 10 0 0 1 . 
Tom  -4 10 0 0 1 . 
Tom  -2 10 0 0 1 . 
Tom   0 10 0 0 1 . 

The first added dose will have a wash-out, thus for clarity an EVID column has been included in the previous example. But of course it is possible to specify a steady-state even if there is no EVID column in the data set. However an II column is mandatory to specify the period between the five added doses to reach steady-state. The absence of this column will throw an exception (see here under for the complete list of exceptions).

Depending on the value of STEADY STATE, a wash-out is done or not for the first dose. Thus, if

  • STEADY STATE = 1, a washout is performed
  • STEADY STATE = 2 or STEADY STATE = 3, a wash-out is not performed

It is possible to find in a data set a mix of steady-state and non steady-state doses. To prevent doses and measurement from colliding, if a normal dose or a measurement is present before a steady-state dose, we stop adding doses not to impact on the result and a warning is thrown. No occasion is generated.

The following data set, with a normal dose at  t=0 and a steady-state dose at t=10 with an interdose-interval of 3.5 will lead to this kind of output

ID TIME Y AMT SS  II 
1 0 . 10 0 0                
1 0 10 . . .
1 1 6 . . .
1 2 3.5 . . .
1 10 . 10 1 3.5
1 11 9 . . .
1 12 6 . . .
1 13 3 . . .
1 14 2 . . .

There will be only 2 additional doses as else wise it would overlay the previous measurements. In addition, there is the wash out (as seen in purple) to start the steady state definition. Moreover, if we replace the SS=1 by SS=2 on line 5, we have the same overlay but no wash out as can be seen in the following figure

ID TIME Y AMT SS  II 
1 0 . 10 0 0                
1 0 10 . . .
1 1 6 . . .
1 2 3.5 . . .
1 10 . 10 2 3.5
1 11 9 . . .
1 12 6 . . .
1 13 3 . . .
1 14 2 . . .

There will be only 2 additional doses as else wise it would overlay the previous measurements. In addition, there is the wash out (as seen in purple) to start the steady state definition.

Remarks

  • In version prior MonolixSuite2018R1, STEADY STATE= 2 and STEADY STATE =3 where not managed.
  • In version prior MonolixSuite2018R1, to prevent doses from colliding, if a normal dose is present before a steady-state dose, a new occasion will be created for the steady-state dose. Thus for the previous example, two occasions would have been created

Format restrictions (an exception will be thrown otherwise):

  • A data set shall not contain more than one column with column-type STEADY STATE.
  • A data set shall not contain more than one column with column-type INTERDOSE INTERVAL.
  • If there is  a column-type STEADY STATE, there should be a column-type INTERDOSE INTERVAL.
  • When a data set contains a column with column-type STEADY STATE there must be a column with column-type INTERDOSE INTERVAL.
  • The column is meaningful only for dose-lines. Its format shall be (for all lines including response-lines for which STEADY STATE information is not applicable) :
    • STEADY STATE shall be either 0 or 1 (‘.’ will be replaced by 0).
    • II shall contain a double value and it shall be positive (or null).
      • when STEADY STATE= 0 then the value shall be null.
      • when STEADY STATE= 1, the value shall be strictly positive.

ADDL: additional dose line

Additional dose lines is a useful shortcut to specify dose regimens with repetitive treatments. ADDL is the number of times the dose shall be repeated and column II contains the dose repetition interval. For instance to specify a dose of 10 every 12 hours during 3 days it is possible to write:

ID TIME AMT 
Tom 0 10
Tom 12 10
Tom 24 10
Tom 36 10
Tom 48 10
Tom 60 10
Tom 72 10

but ADDL and II (interdose-interval) can also be used to specify the same information in a single line

ID TIME AMT ADDL II 
Tom 0 10 6 12

Notice that in the proposed example, ADDL should be at 6 to have 6 additional administrations. This is very useful for periodic treatments. Two important remarks concerning regression values:

  • If there is a regression-column (i.e. a column with column-type REGERSSOR), its value will also be repeated for added doses even though this value has not been specified but obtained via interpolation.
  • When regression values are defined after the first added dose, warnings are generated. Indeed these values will not be repeated and can possibly interfere with automatically added regression values at dose time. So the warning is generated for the user to confirm that its data make sense.

Format restrictions (an exception will be thrown otherwise):

  • ADDL shall only contain positive (or null) integers or “.” (which will be replaced by 0).
  • When there is an ADDL column there must be an INTERDOSE INTERVAL (interdose interval) column to indicate the inter dose timing.
  • For dose-lines with ADDL strictly positive, the INTERDOSE INTERVAL value must be strictly positive.