httk (version 2.6.0)

solve_pbtk_lifestage: Solve the pbtk_lifestage model, which has time-dependent parameters

Description

This function solves for the amounts or concentrations in uM of a chemical in different tissues as functions of time based on the dose and dosing frequency. In this PBTK formulation. \(C_{tissue}\) is the concentration in tissue at time t. Since the perfusion limited partition coefficients describe instantaneous equilibrium between the tissue and the free fraction in plasma, the whole plasma concentration is \(C_{tissue,plasma} = \frac{1}{f_{up}*K_{tissue2fup}}*C_{tissue}\). Note that we use a single, constant value of \(f_{up}\) across all tissues. Corespondingly the free plasma concentration is modeled as \(C_{tissue,free plasma} = \frac{1}{K_{tissue2fup}}*C_tissue\). The amount of blood flowing from tissue x is \(Q_{tissue}\) (L/h) at a concentration \(C_{x,blood} = \frac{R_{b2p}}{f_{up}*K_{tissue2fup}}*C_{tissue}\), where we use a single \(R_{b2p}\) value throughout the body. Metabolic clearance is modelled as being from the total plasma concentration here, though it is restricted to the free fraction in calc_hep_clearance by default. Renal clearance via glomerulsr filtration is from the free plasma concentration. The compartments used in this model are the gutlumen, gut, liver, kidneys, veins, arteries, lungs, and the rest of the body. The extra compartments include the amounts or concentrations metabolized by the liver and excreted by the kidneys through the tubules. AUC is the area under the curve of the plasma concentration.

Usage

solve_pbtk_lifestage(
  chem.name = NULL,
  chem.cas = NULL,
  dtxsid = NULL,
  times = NULL,
  parameters = NULL,
  days = 10,
  tsteps = 4,
  daily.dose = NULL,
  dose = NULL,
  doses.per.day = NULL,
  initial.values = NULL,
  plots = FALSE,
  suppress.messages = FALSE,
  species = "Human",
  iv.dose = FALSE,
  input.units = "mg/kg",
  output.units = NULL,
  default.to.human = FALSE,
  class.exclude = TRUE,
  recalc.blood2plasma = FALSE,
  recalc.clearance = FALSE,
  dosing.matrix = NULL,
  adjusted.Funbound.plasma = TRUE,
  regression = TRUE,
  restrictive.clearance = TRUE,
  minimum.Funbound.plasma = 1e-04,
  Caco2.options = list(),
  monitor.vars = NULL,
  time.varying.params = TRUE,
  start.age = 360,
  gender = c("Male", "Female"),
  weight_category = c("Underweight", "Normal", "Overweight", "Obese"),
  gfr_category = c("Normal", "Kidney Disease", "Kidney Failure"),
  reths = c("Mexican American", "Other Hispanic", "Non-Hispanic White",
    "Non-Hispanic Black", "Other"),
  input.param.dir = NULL,
  ...
)

Value

A matrix of class deSolve with a column for time(in days), each compartment, the area under the curve, and plasma concentration and a row for each time point.

Arguments

chem.name

Either the chemical name, CAS number, or the parameters must be specified.

chem.cas

Either the chemical name, CAS number, or the parameters must be specified.

dtxsid

EPA's DSSTox Structure ID (https://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs

times

Optional time sequence for specified number of days. Dosing sequence begins at the beginning of times.

parameters

Chemical parameters from parameterize_pbtk function, overrides chem.name and chem.cas.

days

Length of the simulation.

tsteps

The number of time steps per hour.

daily.dose

Total daily dose, defaults to mg/kg BW.

dose

Amount of a single, initial oral dose in mg/kg BW.

doses.per.day

Number of doses per day.

initial.values

Vector containing the initial concentrations or amounts of the chemical in specified tissues with units corresponding to output.units. Defaults are zero.

plots

Plots all outputs if true.

suppress.messages

Whether or not the output message is suppressed.

species

Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").

iv.dose

Simulates a single i.v. dose if true.

input.units

Input units of interest assigned to dosing, defaults to mg/kg BW

output.units

A named vector of output units expected for the model results. Default, NULL, returns model results in units specified in the 'modelinfo' file. See table below for details.

default.to.human

Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).

class.exclude

Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE).

recalc.blood2plasma

Recalculates the ratio of the amount of chemical in the blood to plasma using the input parameters, calculated with hematocrit, Funbound.plasma, and Krbc2pu.

recalc.clearance

Recalculates the the hepatic clearance (Clmetabolism) with new million.cells.per.gliver parameter.

dosing.matrix

Vector of dosing times or a matrix consisting of two columns or rows named "dose" and "time" containing the time and amount, in mg/kg BW, of each dose.

adjusted.Funbound.plasma

Uses adjusted Funbound.plasma when set to TRUE along with partition coefficients calculated with this value.

regression

Whether or not to use the regressions in calculating partition coefficients.

restrictive.clearance

Protein binding not taken into account (set to 1) in liver clearance if FALSE.

minimum.Funbound.plasma

Monte Carlo draws less than this value are set equal to this value (default is 0.0001 -- half the lowest measured Fup in our dataset).

Caco2.options

A list of options to use when working with Caco2 apical to basolateral data Caco2.Pab, default is Caco2.options = list(Caco2.Pab.default = 1.6, Caco2.Fabs = TRUE, Caco2.Fgut = TRUE, overwrite.invivo = FALSE, keepit100 = FALSE). Caco2.Pab.default sets the default value for Caco2.Pab if Caco2.Pab is unavailable. Caco2.Fabs = TRUE uses Caco2.Pab to calculate fabs.oral, otherwise fabs.oral = Fabs. Caco2.Fgut = TRUE uses Caco2.Pab to calculate fgut.oral, otherwise fgut.oral = Fgut. overwrite.invivo = TRUE overwrites Fabs and Fgut in vivo values from literature with Caco2 derived values if available. keepit100 = TRUE overwrites Fabs and Fgut with 1 (i.e. 100 percent) regardless of other settings. See get_fbio for further details.

monitor.vars

Which variables are returned as a function of time. The default value of NULL provides "Cgut", "Cliver", "Cven", "Clung", "Cart", "Crest", "Ckidney", "Cplasma", "Atubules", "Ametabolized", and "AUC"

time.varying.params

Whether or not to allow parameters to vary in time according to the nonparametric regression determined by get_input_param_timeseries. Default is TRUE.

start.age

The age of the individual in months at the beginning of the simulation. Default 360.

The next four parameters play the same role here as in httkpop_generate: the user may restrict the data available to generate parameter evolution by specifying demographics.

gender

Optional: The gender categories to include in the popualtion; default c("Female", "Male").

weight_category

Optional: The weight categories to include in the population. Default is c('Underweight', 'Normal', 'Overweight', 'Obese'). User-supplied vector must contain one or more of these strings.

gfr_category

The kidney function categories to include in the population. Default is c('Normal','Kidney Disease', 'Kidney Failure') to include all kidney function levels.

reths

Optional: a character vector giving the races/ethnicities to include in the population. Default is c('Mexican American','Other Hispanic','Non-Hispanic White','Non-Hispanic Black','Other'), to include all races and ethnicities in their proportions in the NHANES data. User-supplied vector must contain one or more of these strings.

input.param.dir

The path to the input_params_data_files directory, which is used to store all input_param data files. If input_params_data_files does not exist, this function will create it in the specified path. Default NULL, in which case the present working directory is used as default.

...

Additional arguments passed to the integrator (deSolve).

Author

Colin Thomson

Details

Note that the model parameters have units of hours while the model output is in days.

Default NULL value for doses.per.day solves for a single dose.

Model Figure

When species is specified as rabbit, dog, or mouse, the function uses the appropriate physiological data(volumes and flows) but substitutes human fraction unbound, partition coefficients, and intrinsic hepatic clearance.

See Also

solve_model

parameterize_pbtk

get_input_param_timeseries

Examples

# \donttest{

params <- parameterize_pbtk(chem.name = 'Bisphenol A')
out <- solve_pbtk_lifestage(chem.name = 'Bisphenol A',
                            parameters = params,
                            days = 365,
                            start.age = 600, # age fifty
                            weight_category=c('Underweight',
                                              'Normal',
                                              'Overweight'),
                            doses.per.day = 3,
                            daily.dose = 1)

# }