Structural model - Two compartment Model for drug and one compartment model for enzyme

Route of administration - IV Infusion

Dosage Regimen - 120 mg of IV infusion with constant rate of 1 hr followed by 9 more doses of 40 mg for 30 minutes duration at the interval of 8 hrs

Number of Subjects - 1

This model gives an understanding of drug pharmacokinetics and *enzyme autoinduction* simultaneously after *repeated IV infusion*.

In this tutorial, you will learn how to build a two compartment model for a drug and one compartment model for an enzyme and simulate from the model.

Call the "necessary" libraries to get started.

using Random using Pumas using PumasUtilities using CairoMakie

In this two compartment model, we administer repeated dose of IV infusion to a single subject.

pk_22 = @model begin @metadata begin desc = "Autoinduction Model" timeu = u"hr" end @param begin "Clearance at Steady State (L/hr)" tvcls ∈ RealDomain(lower=0) "Central Volume of Distribution (L)" tvvc ∈ RealDomain(lower=0) "Peripheral Volume of Distribution (L)" tvvp ∈ RealDomain(lower=0) "Distribution Clearance (L/hr)" tvq ∈ RealDomain(lower=0) "Input Rate Constant for Enzyme (hr⁻¹)" tvkin ∈ RealDomain(lower=0) "Output Rate Constant for Enzyme (hr⁻¹)" tvkout ∈ RealDomain(lower=0) "Initial Enzyme Concentration" tvE0 ∈ RealDomain(lower=0) Ω ∈ PDiagDomain(7) "Proportional RUV" σ²_prop ∈ RealDomain(lower=0) end @random begin η ~ MvNormal(Ω) end @pre begin Cls = tvcls * exp(η[1]) Vc = tvvc * exp(η[2]) Vp = tvvp * exp(η[3]) Q = tvq * exp(η[4]) Kin = tvkin * exp(η[5]) Kout = tvkout * exp(η[6]) E0 = tvE0 * exp(η[7]) end @init begin Enzyme = (Kin/Kout)+ E0 end @dynamics begin Central' = -(Cls/Vc) * Central * Enzyme + (Q/Vp) * Peripheral - (Q/Vc) * Central Peripheral' = (Q/Vc) * Central - (Q/Vp) * Peripheral Enzyme' = Kin * (E0+Central/Vc) - Kout * Enzyme end @derived begin cp = @. Central/Vc """ Observed Concentration (mcg/L)) """ dv ~ @. Normal(cp, sqrt(cp^2*σ²_prop)) end end

PumasModel Parameters: tvcls, tvvc, tvvp, tvq, tvkin, tvkout, tvE0, Ω, σ²_prop Random effects: η Covariates: Dynamical variables: Central, Peripheral, Enzyme Derived: cp, dv Observed: cp, dv

Hereby Parameters are provided for the simulation. `tv`

represents the typical value for parameters.

$tvcls$ - Typical Value Clearance at Steady State (L/hr)

$tvvc$ - Typical Value Central Volume of Distribution (L)

$tvvp$ - Typical Value Peripheral Volume of Distribution (L)

$tvq$ - Typical Value Distribution Clearance (L/hr)

$tvkin$ - Input Rate Constant for Enzyme (hr⁻¹)

$tvkout$ - Output Rate Constant for Enzyme (hr⁻¹)

$tvE0$ - Initial Enzyme Concentration

$Ω$ - Between Subject Variability

$σ$ - Residual errors

param = (tvcls = 0.04, tvvc = 150.453, tvvp = 54.0607, tvq = 97.8034, tvkin = 0.0238896, tvkout = 0.0238896, tvE0 = 132.864, Ω = Diagonal([0.0,0.0,0.0,0.0,0.0,0.0,0.0]), σ²_prop = 0.005)

(tvcls = 0.04, tvvc = 150.453, tvvp = 54.0607, tvq = 97.8034, tvkin = 0.023 8896, tvkout = 0.0238896, tvE0 = 132.864, Ω = [0.0 0.0 … 0.0 0.0; 0.0 0.0 … 0.0 0.0; … ; 0.0 0.0 … 0.0 0.0; 0.0 0.0 … 0.0 0.0], σ²_prop = 0.005)

Dosage Regimen - **120 mg** of IV infusion with constant rate of 1 hr followed by 9 more doses of 40 mg for 30 minutes duration at the interval of 8 hrs

ev1 = DosageRegimen([120000,40000], time = [0,8], duration = [1,0.5], cmt = [1,1], addl = [0,8], ii = [0,8]) sub1 = Subject(id = 1, events = ev1, observations = (cp = nothing,))

Subject ID: 1 Events: 20 Observations: cp: (nothing)

Lets simulate for plasma concentration with the specific observation time points after IV.

Random.seed!(123) sim_sub1 = simobs(pk_22, sub1, param, obstimes=0.00:0.01:96)

f, a, p = sim_plot(pk_22, [sim_sub1], observations = :cp, color = :redsblues, linewidth = 4, axis = (xlabel = "Time (hour)", ylabel = "PK22 Concentrations (μg/mL)", xticks = 0:10:100)) axislegend(a) f