Implementation details • ESQhtpbpk

Generic PBPK model structure

A generic PBPK model will be automatically created for each species, partition coefficient (PC) method, cellular permeability (CP) method, as well as each required combination of processes for the number of compounds used. For each generic model structure the required number of administrations of each type covering all studies using this generic model will be identified and added.

Note: CP calculation method “Charge dependent Schmitt normalized to PK-Sim” is not supported as it is not properly implemented in the current PK-Sim versions (11.3 and 12.0).

Compound

The Compound class is used to create the compound object that will be used in the studies. Several compound properties are already predefined and can be directly used.

The predefined compound properties (with their default values) are:

compound <- Compound$new(ID = "Acetaminophen")
compound
#> • Compound Properties:
#>   • Lipophilicity: 0 Log Units
#>   • Fraction unbound: 1
#>   • Plasma protein binding partner: Albumin
#>   • Is small molecule: 1
#>   • Molecular weight: 100 g/mol
#>   • Bromine count: 0
#>   • Chlorine count: 0
#>   • Fluorine count: 0
#>   • Iodine count: 0
#>   • pKa value 0: 0
#>   • Compound type 0: Neutral
#>   • pKa value 1: 0
#>   • Compound type 1: Neutral
#>   • pKa value 2: 0
#>   • Compound type 2: Neutral
#>   • Reference pH: 7
#>   • Solubility: 1 mg/l
#> • Compound Methods:
#>   • Partition Coefficient Method: PK-Sim Standard
#>   • Cellular Permeability Method: PK-Sim Standard

Compound Properties

Predefined compound properties can be easily changed with the setPropertyValue method

compound$setPropertyValue("Molecular weight", 151.16, unit = "g/mol")

Additional compound properties can be added as needed using addProperty methods (with corresponding paths when using predefined PKML files). The property name serves as an alias for easy access in the compound object. The parName must match the parameter name as defined in PK-Sim.

compound$addProperty(
  name = "Pint", 
  parName = "Intestinal permeability (transcellular)",
  dimension = "Velocity",
  value = 2e-5,
  unit = "cm/min"
)

compound
#> • Compound Properties:
#>   • Lipophilicity: 0 Log Units
#>   • Fraction unbound: 1
#>   • Plasma protein binding partner: Albumin
#>   • Is small molecule: 1
#>   • Molecular weight: 151.16 g/mol
#>   • Bromine count: 0
#>   • Chlorine count: 0
#>   • Fluorine count: 0
#>   • Iodine count: 0
#>   • pKa value 0: 0
#>   • Compound type 0: Neutral
#>   • pKa value 1: 0
#>   • Compound type 1: Neutral
#>   • pKa value 2: 0
#>   • Compound type 2: Neutral
#>   • Reference pH: 7
#>   • Solubility: 1 mg/l
#>   • Pint: 2e-05 cm/min
#> • Compound Methods:
#>   • Partition Coefficient Method: PK-Sim Standard
#>   • Cellular Permeability Method: PK-Sim Standard

When adding property to compound and using a predefined PKML file, the user also needs to specify the corresponding path in the PKML model.

Compound Processes

When creating generic models automatically, the user can add processes to the compound using the addProcessProperty method. This requires to specify to which process type the parameter belongs to.

## add various processes to a compound by adding required process properties
compound$addProcessProperty(
  processType = "Liver Plasma Clearance",
  propertyName = "Plasma clearance",
  parName = "Plasma clearance",
  dimension = "Flow per weight",
  value = 0.27, 
  unit = "L/h/kg"
)

compound
#> • Compound Properties:
#>   • Lipophilicity: 0 Log Units
#>   • Fraction unbound: 1
#>   • Plasma protein binding partner: Albumin
#>   • Is small molecule: 1
#>   • Molecular weight: 151.16 g/mol
#>   • Bromine count: 0
#>   • Chlorine count: 0
#>   • Fluorine count: 0
#>   • Iodine count: 0
#>   • pKa value 0: 0
#>   • Compound type 0: Neutral
#>   • pKa value 1: 0
#>   • Compound type 1: Neutral
#>   • pKa value 2: 0
#>   • Compound type 2: Neutral
#>   • Reference pH: 7
#>   • Solubility: 1 mg/l
#>   • Pint: 2e-05 cm/min
#> • Compound Processes:
#>   • Liver Plasma Clearance
#>     • Plasma clearance: 0.27 L/h/kg
#> • Compound Methods:
#>   • Partition Coefficient Method: PK-Sim Standard
#>   • Cellular Permeability Method: PK-Sim Standard

Formulations

Formulations can be defined using the various helper functions provided: - createDissolvedFormulation - createWeibullFormulation
- createLint80Formulation - createParticleDissolutionFormulation - createZeroOrderFormulation - createFirstOrderFormulation

weibull_form <- createWeibullFormulation(
  name = "Weibull",
  lagTime = 30,
  lagTimeUnit = "min",
  dissolutionTime50 = 60,
  dissolutionTime50Unit = "min"
)

weibull_form
#> Formulation Name: Weibull
#> Formulation Type: Weibull
#>   • Dissolution time (50% dissolved): 60 min
#>   • Lag time: 30 min
#>   • Dissolution shape: 0.92
#>   • Use as suspension: 1

Administration protocols

The SimpleProtocol class is used to define simple administration protocols for the studies. If a formulation is needed it can be associated with the protocol using the setFormulation method.

protocol <- SimpleProtocol$new(
  route = "Oral",
  dosingInterval = "24",
  dose = 1,
  doseUnit = "mg/kg",
  startTime = 0,
  startTimeUnit = "h",
  endTime = 48,
  endTimeUnit = "h"
)
#> Warning: No `WaterVolPerBW` provided, using default value of 3.5 ml/kg.
#> Warning: No `Formulation` provided, using default of dissolved.
#> Formulation can be changed with `protocolObject$setFormulation(formulation)`.

protocol$setFormulation(formulation = weibull_form)
protocol
#>   • Route: Oral
#>   • Dose: 1 mg/kg
#>   • Dose Interval: Once each 24 hours
#>   • Start Time: 0 h
#>   • End Time: 48 h
#>   • Volume of water per body weight: 3.5 ml/kg
#>   • Formulation: Weibull

Additionally, for more complex dosing strategies, advanced protocols can be created with the AdvancedProtocol class. To do so, first an advanced protocol needs to be initialized with the AdvancedProtocol$new function. Then repetitions schemas need to be defined with addSchema method and associated with single dose protocol using addProtocolToSchema method. These will follow the schema repetition strategy defined during the addSchema step.

protocol <- AdvancedProtocol$new()
protocol$addSchema(
  schemaName = "Loading Dose", 
  timeUnit = "h", 
  timeBetweenRepetitions = 0, 
  numberOfRepetitions = 1, 
  startTime = 0
)
protocol$addSchema(
  schemaName = "Maintenance Dose", 
  timeUnit = "h", 
  timeBetweenRepetitions = 12, 
  numberOfRepetitions = 5, 
  startTime = 12
)

ivLoading <- SimpleProtocol$new(route = "IV Infusion", dose = 10, doseUnit = "mg")
#> Warning: No `infusionTime` provided, using default value of 60 minutes.
ivMaintenance <- SimpleProtocol$new(route = "IV Bolus", dose = 1, doseUnit = "mg")

protocol$addProtocolToSchema(schemaName = "Loading Dose", protocol = ivLoading)
protocol$addProtocolToSchema(schemaName = "Maintenance Dose", protocol = ivMaintenance)

protocol
#> Schema: Loading Dose
#>   • Start time: 0 h
#>   • Number of repetitions: 1
#>   • Time between repetitions: 0 h
#>   Schema item 1
#>     • Route: Intravenous infusion
#>     • Dose: 10 mg
#>     • Dose Interval: Single Dose
#>     • Start Time: 0 h
#>     • Infusion Time: 60 min
#> Schema: Maintenance Dose
#>   • Start time: 12 h
#>   • Number of repetitions: 5
#>   • Time between repetitions: 12 h
#>   Schema item 1
#>     • Route: Intravenous bolus
#>     • Dose: 1 mg
#>     • Dose Interval: Single Dose
#>     • Start Time: 0 h