solve_fetal_pbtk: Solve_fetal_PBTK

In httk: High-Throughput Toxicokinetics

Solve_fetal_PBTK

Description

This function solves for the amounts or concentrations in uM of a chemical in different tissues of a maternofetal system 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 maternal compartments used in this model are the gut lumen, gut, liver, venous blood, arterial blood, lung, adipose tissue, kidney, thyroid, and rest of body. A placenta is modeled as a joint organ shared by mother and fetus, through which chemical exchange can occur with the fetus. Fetal compartments include arterial blood, venous blood, kidney, thyroid, liver, lung, gut, brain, and rest of 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_fetal_pbtk(
  chem.name = NULL,
  chem.cas = NULL,
  dtxsid = NULL,
  times = seq(13 * 7, 40 * 7, 1),
  parameters = NULL,
  days = NULL,
  species = "human",
  tsteps = 4,
  dose = NULL,
  dosing.matrix = NULL,
  daily.dose = NULL,
  doses.per.day = NULL,
  initial.values = NULL,
  plots = FALSE,
  suppress.messages = FALSE,
  iv.dose = FALSE,
  input.units = "mg/kg",
  output.units = NULL,
  default.to.human = FALSE,
  recalc.blood2plasma = FALSE,
  recalc.clearance = FALSE,
  adjusted.Funbound.plasma = TRUE,
  regression = TRUE,
  restrictive.clearance = TRUE,
  minimum.Funbound.plasma = 1e-04,
  monitor.vars = NULL,
  atol = 1e-08,
  rtol = 1e-08,
  ...
)

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 in days. Dosing sequence begins at the beginning of times. Default is from 13th week of pregnancy to 40th due to data constraints.
parameters	Chemical parameters from parameterize_fetal_pbtk function, overrides chem.name and chem.cas.
days	Length of the simulation.
species	Included for compatibility with other functions, but the model will not run for non-human species (default "Human").
tsteps	The number time steps per hour. Default of 4.
dose	Amount of a single, initial oral dose in mg/kg BW.
dosing.matrix	A matrix of either one column (or row) with a set of dosing times or with two columns (or rows) correspondingly named "dose" and "time" containing the time and amount, in mg/kg BW, of each dose.
daily.dose	Total daily dose, 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 compartment.units. Defaults are zero.
plots	Plots all outputs if true.
suppress.messages	Whether or not the output message is suppressed.
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).
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.
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).
monitor.vars	Which variables to track by default
atol	Absolute tolerance used by integrator (deSolve) to determine numerical precision– defaults to 1e-8.
rtol	Relative tolerance used by integrator (deSolve) to determine numerical precision – defaults to 1e-8.
...	Additional arguments passed to the integrator.

Details

The stage of pregnancy simulated here begins by default at the 13th week due to a relative lack of data to support parameterization prior, in line with the recommendations of Kapraun et al. 2019 ("Empirical models for anatomical and physiological..."), and ends at the 40th week of pregnancy.

Note that the model parameters have units of hours while the model output is in days. Dose is in mg, not scaled for body weight.

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

This gestational model is only parameterized for humans.

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.

Author(s)

John Wambaugh, Mark Sfeir, and Dustin Kapraun

See Also

solve_model

parameterize_fetal_pbtk

Examples

out = solve_fetal_pbtk(chem.name = 'bisphenol a', daily.dose = 1,
doses.per.day = 3)

# With adjustement to fraction unbound plasma for fetus:
fetal_parms_fup_adjusted <- 
  parameterize_fetal_pbtk(chem.name = "triclosan")
head(solve_fetal_pbtk(parameters = fetal_parms_fup_adjusted))
 
# Without adjustement to fraction unbound plasma for fetus:
fetal_parms_fup_unadjusted <-  
  parameterize_fetal_pbtk(chem.name = "triclosan",
                          fetal_fup_adjustment = FALSE)
head(solve_fetal_pbtk(parameters = fetal_parms_fup_unadjusted))

httk documentation built on Sept. 11, 2024, 9:32 p.m.