Administration Protocols

An administration protocol is a set of data describing administration type, dose, and dosing regimen. These properties can be specified within the building block Administration Protocol . Administration protocols can be saved as templates and shared among other projects and users.

Definition of new Administration Protocols in PK-Sim®

To create a new administration protocol, do one of the following:

• Click Administration Protocol in the Create Group of the Modeling Tab, or

• Right mouse click on Administration Protocols in the Building Blocks Explorer and select Add Administration Protocol..., or

• Use the short cut Ctrl+Alt+A

A new window will open where you can define your administration protocol. You can choose between Simple protocol and Advanced protocol. To switch between these two views, select the respective protocol type in the uppermost checkboxes of the window.

Note that when switching between simple and advanced protocol, some of the already defined parameters will be reset. When switching from simple to advanced protocol, the dosing schedule will be transferred. This is not true for the opposite direction.

Simple protocol, drug administration via different routes can be defined by means of a single or predefined multiple dosing scheme.

Advanced protocol, multiple dosing regimens and treatment cycles of any scheme and combination can be defined.

The default is the Simple Protocol . In both options, the dose and dosing scheme are visualized in the lower panel of the window. Depending on the dose unit selected, the Y-axis description will change accordingly.

The administration protocol is initialized by providing it a Name in the respective input field. The name is used to identify the protocol when its parameters are saved in the project and/or as a template. Then, choose between Simple protocol and Advanced protocol and set the properties of the protocol.

Simple Protocol

To create a Simple Protocol, follow the instructions in the table below.

Depending on the choice of administration protocol the required input parameters change.

Administration Type	Description
Intravenous Bolus	1. Select the administration type Intravenous Bolus from the drop-down menu 2. Enter the dose and select the appropriate dose unit from the drop-down menu 3. Select the appropriate dosing interval from the drop-down menu 4. In case a multiple dosing regimen is selected, the protocol end time has to be defined. 5. Confirm and close window by clicking OK
Intravenous Infusion	1. Select the administration type Intravenous Infusion from the drop-down menu 2. Enter the dose and select the appropriate dose unit from the drop-down menu 3. Select the appropriate dosing interval from the drop-down menu 4. In case a multiple dosing regimen is selected, the protocol end time has to be defined. 5. Enter the infusion time and select the appropriate time unit from the drop-down menu 6. Confirm and close window by clicking OK
Oral	1. Select the administration type Oral from the drop-down menu 2. Enter the dose and select the appropriate dose unit from the drop-down menu. 3. Select the appropriate dosing interval from the drop-down menu. 4. In case a multiple dosing regimen is selected, the protocol end time has to be defined. 5. Enter the volume of water co-administered. The default is 3.5 mL/kg body weight, which corresponds to a volume of 250 mL (8-9 fl. oz.) of water for an average human. This volume is also considered appropriate in animal dosing [103]. However, if desired, the liquid volume can be adjusted according to the protocol of the (pre)clinical study. 6. Confirm and close window by clicking OK

Please note that if the administration type Oral is selected this will require the definition of a Formulation in the Formulation building block for the Simulation.

Administration Type

Description

User Defined

1. Select the administration type User Defined from the drop- down menu 2. Enter the dose and select the appropriate dose unit from the drop-down menu. 3. Select the appropriate dosing interval from the drop-down menu. 4. In case a multiple dosing regimen is selected, the protocol end time has to be defined. 5. Enter the target organ into which the drug is to be administered, e.g., Muscle in the case of intramuscular administration. 6. Enter the target compartment within the target organ into which the drug is to be administered, e.g., "Interstitial" in the case of intramuscular administration. 7. Confirm and close window by clicking OK

Please note that in case that the administration type User Defined is selected this will require the definition of a Formulation in the Formulation building block for the Simulation.

Events in a Simple Protocol

In addition to the administration, one event - e.g., a meal or the emptying of the gallbladder - can be defined in a simple protocol. This covers the typical situations in which a drug is administered before, with, or after a meal, and it avoids having to add a recurring event to every simulation individually.

1. Activate Add an event for every administration....

2. Enter the Event offset, i.e., the time of the event relative to the corresponding administration.

The event is repeated together with the administration, so that a multiple dosing regimen with a meal at every administration only has to be defined once. Which event building block is used for the event is decided when the simulation is created, see Events.

Where administrations end up in the simulation. In the created simulation, every administration is nested under a container named after the formulation it uses. The administration types that require no formulation — Intravenous Bolus and Intravenous Infusion — are nested under a container named No formulation, so that all administrations have the same structure. The path of an application parameter is therefore

Events|<protocol name>|<formulation or "No formulation">|Application_<n>|ProtocolSchemaItem|<parameter>

for example Events|iv 5 mg|No formulation|Application_1|ProtocolSchemaItem|Infusion time. The No formulation container was introduced in version 13; paths stored in projects created with earlier versions are missing it — see Changed paths in PK-Sim modules.

Advanced Protocol

Activate Advanced protocol in the Create Administration Protocol window.

In the uppermost drop-down menu, the time unit for visualization of dose and dosing scheme in the lower panel of the window can be selected. Depending on the dose unit(s) selected, the Y-axis label(s) will change appropriately.

The table used to defined the advanced protocol consists of the following five columns:

1. The Start Time at which the protocol schema starts.

2. The Number of Repetitions defining the iterations of the protocol schema.

3. The Time Between Repetitions defining the time lag between the iterations of several protocol schemata.

4. The End Time defining the end time of the protocol schema. The end time is automatically calculated based on the input parameters.

5. In the last column, additional protocol schemata can be added by clicking or deleted by clicking . Please note that at least one protocol schema needs to be defined. The various protocol schemata will automatically be re-sorted according to the protocol schema start time.

The secondary table, can be opened by clicking in the column Start Time, a number of individual schema items can be defined for the given protocol schema. The following five columns can be found:

1. The Start Time of schema items in relation to the start time of the protocol schema. If the start time of the schema items is 0, the administration time equals the start time of the protocol schema.

2. The Dose in units mg or mg/kg of the drug administered.

3. The Type. You can choose from the following administration or event types from the drop-down menu:

   • Intravenous Bolus

   • Intravenous Infusion: requires the input of the Infusion time in units min, h, or s

   • Oral: requires the input of the Volume of water/body weight co-administered, which is 3.5 mL/kg BW per default (see PK- Sim® - Formulations) and, additionally, the definition of a Placeholder for formulation in column 4.

   • User defined: requires the input of the Target organ and Target compartment.

   • Event: schedules an event instead of an administration, see Events in an Advanced Protocol.

4. Placeholder, holding the placeholder for the formulation of an administration and the placeholder for the event of an event entry. For an intravenous administration (Intravenous Bolus and Intravenous Infusion), the definition of a formulation placeholder is not necessary, because the drug is always assumed to be dissolved when given intravenously (see PK-Sim® - Formulations).

In case of oral and user defined administration, you should add a note on the type of formulation. Later, in the simulation, the formulation placeholder can be matched with the corresponding Formulation building block. This may sound trivial in the case of only one formulation given repeatedly at the given times. However, consider that you can set up sophisticated dosing schedules, in which various administration types and formulations are administered at various times. Then, the formulation type should already be signified in the administration protocol in order to be able to appropriately match the schedules with the various formulations. For further information please see PK-Sim® - Simulations.

1. In the last column, additional dosing schedules can be added or deleted by clicking. Please note that at least one dosing schedule needs to be defined for each protocol scheme. The various schema items will automatically be re-sorted according to the schema item start time.

Example

In the following screenshot, an example of an advanced protocol is given. The protocol example consists of only one protocol scheme. However, the protocol schema is repeated after 24 hours. Within one repetition, the drug is administered three times: first, an intravenous bolus loading dose of 1 mg/kg is given; second, an immediate release (IR) tablet containing 50 mg of drug is given 2 hours later; third, an enteric coated (EC) tablet containing 50 mg of the drug is given 12 hours after the intravenous dose, i.e. 12 hours after the beginning of the protocol schema. The dissolution profiles of the two formulation types have to be defined in the Formulation building block. The formulations can be imported and linked to the corresponding administration time points during the generation of the simulation. Here, only a "placeholder" has to be defined that can be used during the generation of the simulation to identify the different tablet types and thus, to appropriately match the administration time points and the formulation types. Since the last dose within the protocol items is administered after 12 hours and the protocol schema is repeated two times with a time between the repetitions of 24 hours, the last dose is administered after 24 + 12 = 36 hours (End Time of the protocol schema). This is also shown in the lower panel of the window.

The Create Administration Protocol dialog. Here, the example of an individually created advanced protocol is shown.

Please note that the combination of the Type User defined and the Advanced protocol is not available.

Events in an Advanced Protocol

Events are entered as schema items with the Type set to Event: the Dose cell is then disabled and the Placeholder cell offers the event placeholders instead of the formulation placeholders. Events defined in this way follow the repetition pattern of the protocol schema, i.e., an event that is defined once is repeated with every repetition of the schema. The preview in the lower panel of the window shows administrations and events on the same time axis.

Events in a Simulation

Events that are defined in an administration protocol are placeholders, in the same way as the placeholders for formulations. They are mapped to Events building blocks of the project in the Administration step of the simulation configuration, together with the other protocol-related mappings. Selecting <None> means that no event is created for the placeholder. The same administration protocol can therefore be used with different events in different simulations.

The Events tab of the simulation configuration is still available. Events that are not linked to an administration, as well as simulations created with previous versions, continue to work unchanged.

Setting or Changing Administration Protocol Properties

To set or change the properties of an existing administration protocol:

1. Right mouse click on the respective administration protocol in the Building Block Explorer

2. Select Edit...

or Double click on the administration protocol in the Building Block Explorer

A window with the current settings will open where properties can be set appropriately. The changes are saved by closing the window by clicking on .

Please note that when you switch between simple and advanced protocol, this action will reset several parameters already defined. However, when switching from simple to advanced protocol, the dosing schedule will be transferred. This does not apply to the opposite direction.

Cloning Administration protocols

To clone a protocol in the project:

1. Right mouse click on the respective protocol in the Building Block Explorer

2. Select Clone...

3. Set an alternative name for the protocol clone and, if desired, enter a description

4. Confirm and close the window by clicking OK

Saving an Administration Protocols as Templates

For each project, a number of administration protocols can be defined. They can be saved as a template and then be shared among several projects and users.

To save an existing administration protocol as template:

1. Right mouse click on the respective administration protocol in the Building Block Explorer

2. Select Save as Template.... If a protocol with the same name already exists, a warning appears and you have the following options:

• Override: This action will override the existing template.

• Save as: You can save the protocol under a different name. In this case, you will be asked to Rename the new template.

• Cancel: This action will abort the saving process.

Loading Existing Administration Protocols from Templates

To load an existing administration protocol from the template database:

1. Right mouse click on Administration Protocols in the Building Block Explorer

2. Select Load From Template...

3. Select the desired administration protocol from the user templates. In case a protocol with the same name already exists in the project, a warning appears and you will have to Rename the protocol that is to be loaded from template.

4. Click OK

The selected administration protocol will appear in the Building Block Explorer.

Administration protocols can also be directly loaded from the template database within a simulation.

Deleting Administration Protocols

To delete an administration protocol from the project:

1. Right mouse click on the respective administration protocol in the Building Block Explorer

2. Select Delete...

3. Confirm by clicking Yes

Please note that a protocol that is used in any simulation of the project cannot be deleted.