Background

• Structural Model - One Compartment Model with Nonlinear elimination.

• Route of administration - IV bolus

• Dosage Regimen - 25 mg, 100 mg

• Number of Subjects - 2

Learing Outcome

This is a one compartment model for IV bolus dose with capacity limited elimination. Concentration time profile was obtained for two subjects with different dosage regimen and different Vmax and Km values.

Objectives

In this tutorial, you will learn how to build one compartment model for IV bolus dose with capacity limited elimination.

Libraries

call the "necessary" libraries to get start.

using Pumas
using Plots
using CSV
using StatsPlots
using Random

Model

pk_20        = @model begin
  @param   begin
    tvvc     ∈ RealDomain(lower=0)
    tvkm     ∈ RealDomain(lower=0)
    tvvmax   ∈ RealDomain(lower=0)
    Ω        ∈ PDiagDomain(3)
    σ²_prop  ∈ RealDomain(lower=0)
  end

  @random begin
    η        ~ MvNormal(Ω)
  end

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

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

  @derived begin
    cp       = @. Central/Vc
    dv       ~ @. Normal(cp, sqrt(cp^2*σ²_prop))
  end
end

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

Parameters

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

• Km - Michaelis menten Constant (μg/L)

• Vc - Volume of Central Compartment (L),

• Vmax - Maximum rate of metabolism (μg/hr),

• Ω - Between Subject Variability,

• σ - Residual error

Note:-

• param1 are the parameter values for Subject 1

• param2 are the parameter values for Subject 2

param1 = (tvkm    = 261.736,
          tvvmax  = 36175.1,
          tvvc    = 48.9892,
          Ω       = Diagonal([0.0,0.0,0.0]),
          σ²_prop = 0.01)

(tvkm = 261.736, tvvmax = 36175.1, tvvc = 48.9892, Ω = [0.0 0.0 0.0; 0.0 0.
0 0.0; 0.0 0.0 0.0], σ²_prop = 0.01)

param2 = (tvkm    = 751.33,
          tvvmax  = 36175.1,
          tvvc    = 48.9892,
          Ω       = Diagonal([0.0,0.0,0.0]),
          σ²_prop = 0.01)

(tvkm = 751.33, tvvmax = 36175.1, tvvc = 48.9892, Ω = [0.0 0.0 0.0; 0.0 0.0
 0.0; 0.0 0.0 0.0], σ²_prop = 0.01)

Dosage Regimen

• Subject1 - receives an IV dose of 25 mg or 25000 μg

• Subject2 - recieves an IV dose of 100 mg or 100000 μg

ev1  = DosageRegimen(25000, time=0, cmt=1)
sub1 = Subject(id=1, events=ev1)
ev2  = DosageRegimen(100000, time=0, cmt=1)
sub2 = Subject(id=2, events=ev2)

Simulation

Simulate the plasma drug concentration for both the subjects

## Subject 1
Random.seed!(123)
sim_sub1 = simobs(pk_20, sub1, param1, obstimes=0.01:0.01:2)
df1      = DataFrame(sim_sub1)

##Subject 2
Random.seed!(123)
sim_sub2 = simobs(pk_20, sub2, param2, obstimes=0.01:0.01:8)
df2      = DataFrame(sim_sub2)

Plot

df1_dv = filter(x -> x.time in [0.08,0.25,0.5,0.75,1,1.5,2], df1)
df2_dv = filter(x -> x.time in [0.08,0.25,0.5,0.75,1,1.5,2,4,6,8], df2)

@df df1 plot(:time, :cp, yaxis=:log,
              title= "Plasma Concentration vs Time", label = "Pred - Conc Sub1 (25mg)",
              xlabel= "Time (hr)", ylabel = "Concentration (ug/L)", linewidth=3,
              xticks=[0,1,2,3,4,5,6,7,8], xlims=(-0.05,8.2), yticks=[10,100,1000,10000], ylims=(10,10000))
@df df2 plot!(:time, :cp, label = "Pred - Conc Sub2 (100mg)", linewidth=3)
@df df1_dv scatter!(:time, :dv, label = "Obs - Conc Sub1 (25mg)")
@df df2_dv scatter!(:time, :dv, label = "Obs - Conc Sub2 (100 mg)")

---