PK41 - Multiple Intravenous Infusions: NCA vs Regression

1 Background

Structural Model - One compartment model with non-linear elimination.
Route of administration - IV infusion
Dosage Regimen - 310 μg, 520 μg, and 780 μg
Number of Subjects - 3

2 Learning Outcome

This is a one compartment model with capacity limited elimination. The concentration time profile was obtained for three subjects administered with three different dosage regimens.

3 Objectives

In this tutorial, you will learn how to build a one compartment model with non-linear elimination.

4 Libraries

Call the necessary libraries to get started.

using Random
using Pumas
using PumasUtilities
using CairoMakie
using AlgebraOfGraphics
using DataFramesMeta
using CSV
using Dates

5 Model

The following model describes the parameters and the differential equation for a one-compartment model with capacity limited elimination

pk_41 = @model begin
    @metadata begin
        desc = "One Compartment Model"
        timeu = u"hr"
    end

    @param begin
        """
        Maximum Metabolic Rate (μg/kg/hr)
        """
        tvvmax ∈ RealDomain(lower = 0)
        """
        Michaelis Menten Constant (μg/kg/L)
        """
        tvkm ∈ RealDomain(lower = 0)
        """
        Volume of Central Compartment (L/kg)
        """
        tvvc ∈ RealDomain(lower = 0)
        Ω ∈ PDiagDomain(3)
        """
        Proportional RUV
        """
        σ²_prop ∈ RealDomain(lower = 0)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @pre begin
        Vmax = tvvmax * exp(η[1])
        Km = tvkm * exp(η[2])
        Vc = tvvc * exp(η[3])
    end

    @dynamics begin
        Central' = -(Vmax * (Central / Vc) / (Km + (Central / Vc)))
    end

    @vars begin
        cp = Central / Vc
    end

    @derived begin
        """
        Observed Concentrations (μg/L)
        """
        dv ~ @. Normal(cp, sqrt(cp^2 * σ²_prop))
    end

    @observed begin
        nca := @nca cp
        cl = NCA.cl(nca)
    end
end

PumasModel
  Parameters: tvvmax, tvkm, tvvc, Ω, σ²_prop
  Random effects: η
  Covariates:
  Dynamical system variables: Central
  Dynamical system type: Nonlinear ODE
  Derived: dv, cp
  Observed: dv, cl, cp

6 Parameters

The parameters are as given below. Note that tv represents the typical value for parameters.

Vmax - Maximum Metabolic Rate (μg/kg/hr)
Km - Michaelis Menten Constant (μg/kg/L)
Vc - Volume of Central compartment (L/kg)

param = (
    tvvmax = 180.311,
    tvkm = 79.8382,
    tvvc = 1.80036,
    Ω = Diagonal([0.04, 0.04, 0.04]),
    σ²_prop = 0.015,
)

7 Dosage Regimen

All subjects receive an IV infusion over 5 hours with the following doses:

Subject 1 receives a dose of 310 μg
Subject 2 receives a dose of 520 μg
Subject 3 receives a dose of 780 μg

dose = [310, 520, 780]

rate_ind = [62, 104, 156]

ids = ["310 μg.kg-1", "520 μg.kg-1", "780 μg.kg-1"]

ev(dose, rate) = DosageRegimen(dose; cmt = 1, time = 0, rate, route = NCA.IVInfusion)

ev (generic function with 1 method)

pop3_sub =
    map((id, dose, rate) -> Subject(; id, events = ev(dose, rate)), ids, dose, rate_ind)

Population
  Subjects: 3
  Observations:

8 Simulation

Simulate the plasma concentration of the drug for all the subjects

Random.seed!(123)

The random effects are zero’ed out since we are simulating a single subject

zfx = zero_randeffs(pk_41, pop3_sub, param)

3-element Vector{@NamedTuple{η::Vector{Float64}}}:
 (η = [0.0, 0.0, 0.0],)
 (η = [0.0, 0.0, 0.0],)
 (η = [0.0, 0.0, 0.0],)

time_values = 0.1:0.01:10
sim_pop3_sub = simobs(pk_41, pop3_sub, param, zfx, obstimes = time_values)

Simulated population (Vector{<:Subject})
  Simulated subjects: 3
  Simulated variables: dv, cp

9 Visualization

We will build a DataFrame to facilitate plotting

df_plot = DataFrame(sim_pop3_sub; include_events = false)

layer =
    data(df_plot) *
    mapping(:time => "Time (hours)", :cp => "Concentration (μg/L)", color = :id => "Dose") *
    visual(Lines; linewidth = 4)
draw(
    layer;
    figure = (; fontsize = 22),
    axis = (;
        xticks = 0:10,
        yscale = log10,
        ytickformat = i -> (@. string(round(i; digits = 1))),
    ),
    legend = (; position = :bottom),
)

layer =
    data(unique(df_plot, [:id, :cl])) *
    mapping(:id => nonnumeric => "Dose", :cl => "Cl (L/hr/kg)") *
    visual(ScatterLines, linewidth = 4, markersize = 22)
draw(layer; axis = (; yticks = 0.8:0.2:1.8,), figure = (; fontsize = 22))

10 Simulating a Population

par = (
    tvvmax = 180.311,
    tvkm = 79.8382,
    tvvc = 1.80036,
    Ω = Diagonal([0.0462, 0.0628, 0.0156]),
    σ²_prop = 0.0234,
)

ids = 1:60
doses = repeat([310, 520, 780]; inner = 20)
rates = repeat([62, 104, 156]; inner = 20)
pop = map(ids, doses, rates) do id, dose, rate
    events = DosageRegimen(dose; cmt = 1, time = 0, rate, route = NCA.IVInfusion)
    return Subject(; id, events)
end

Random.seed!(1234)
sim_pop = simobs(pk_41, pop, par, obstimes = [0, 0.1, 2, 5, 6, 8, 10])

df_sim = select(DataFrame(sim_pop; include_events = false), [:id, :time, :cp, :cl])

CSV.write("pk_41.csv", df_sim)

"pk_41.csv"