Structural model - One compartment Oral administration consists of time dependent change in the elimanation rate constant.

Route of administration - Oral

Dosage Regimen - Nortriptyline (NT) 10 mg (or 10000 μg) Oral, three times daily for 29 days (i.e. 696 hours), after 216 hours treatment with an enzyme inducer i.e. Pentobarbital (PB) for a period of 300 hours i.e up till 516 hours of treatment with NT.

Number of Subjects - 1

By the application of the present model, we will learn how to simulate model for heteroinduction having first order input/ output model to repeated oral dose data on treatment with an enzyme inducer for a limited duration and how to develop a better fit for the available data.

In this exercise you will learn how to

Simulate an Oral One Compartment with an enzyme induction consists of time dependent change in the elimination rate constant.

Certain assumptions to be considered:

The fractional turnover rate i.e. Kout of the enzyme has a longer half-life than the drug or the inducer

The duration from one level of enzyme activity to other will be influenced by Kout of the enzyme

The Kout is not regulated by the PB. The interpretation V includes bioavailability (i.e., it is really V/F).

Write a differential equation for a

*one-compartment model*with*oral absorption*including time dependent change in elimination rate constant.

call the "necessary" libraries to get start.

using Pumas using Plots using CSV using StatsPlots using Random

In this one compartment model, we administer dose in Depot compartment at *'time= 0'* that is given every *'8 hours'* for *'87 additional doses'*. A second drug which is an enzyme inducer (Pentobarbital) is added at 216 hrs for 300 hrs up to 516 hours of treatment with NT.

**Note:-** We do not have concentrations of Pentobarbital and hence it is not included in the model.

pk_21 = @model begin @param begin tvka ∈ RealDomain(lower=0) tvclss ∈ RealDomain(lower=0) tvlag ∈ RealDomain(lower=0) tvclpre ∈ RealDomain(lower=0) tvkout ∈ RealDomain(lower=0) tvv ∈ RealDomain(lower=0) Ω ∈ PDiagDomain(3) σ²_prop ∈ RealDomain(lower=0) end @random begin η ~ MvNormal(Ω) end @covariates TBP TBP2 @pre begin Ka = tvka * exp(η[1]) Clpre = tvclpre * exp(η[3]) # Preinduction Clearance Clss = tvclss * exp(η[2]) # Postinduction Clearance lags = (Depot=tvlag,) Vc = tvv Kout = tvkout Kpre = Clpre/Vc Kss = Clss/Vc Kperi = Kss-(Kss-Kpre)*exp(-Kout*(t-TBP)) A = Kss - (Kss-Kpre)*exp(-Kout*(TBP2-TBP)) Kpost = Kpre - (Kpre-A)*exp(-Kout*(t-TBP2)) K10 = (t<TBP) * Kpre + (t>=TBP && t<TBP2) * Kperi + (t>=TBP2) * Kpost end @dynamics begin Depot' = -Ka*Depot Central' = Ka*Depot - K10*Central end @derived begin cp = @. (1000/263.384)*Central/Vc dv ~ @. Normal(cp, sqrt(cp^2*σ²_prop)) end end

PumasModel Parameters: tvka, tvclss, tvlag, tvclpre, tvkout, tvv, Ω, σ²_prop Random effects: η Covariates: TBP, TBP2 Dynamical variables: Depot, Central Derived: cp, dv Observed: cp, dv

The parameters are as given below. `tv`

represents the typical value for parameters.

Ka - Absorption Rate Constant (1/hr)

CLss - Intrinsic Clearance post-treatment (L/hr),

tlag - Lag-time (hrs),

CLpre - Intrinsic Clearance pre-treatment (L/hr),

Kout - Fractional turnover rate (1/hr),

V - Volume of distribution (L),

Ω - Between Subject Variability,

σ - Residual error.

param = ( tvka = 1.8406, tvclss = 114.344, tvlag = 0.814121, tvclpre = 46.296, tvkout = 0.00547243, tvv = 1679.4, Ω = Diagonal([0.0,0.0,0.0]), σ²_prop = 0.015)

(tvka = 1.8406, tvclss = 114.344, tvlag = 0.814121, tvclpre = 46.296, tvkou t = 0.00547243, tvv = 1679.4, Ω = [0.0 0.0 0.0; 0.0 0.0 0.0; 0.0 0.0 0.0], σ²_prop = 0.015)

In this section the Dosage regimen is mentioned for:

Oral dosing of

**10 mg or 10000 μg**at`time=0`

that is given every`8 hours`

for`87 additional doses`

for a single subject.

ev1 = DosageRegimen(10000, cmt=1, time=0, ii=8, addl=87) sub1 = Subject(id=1, events=ev1, covariates=(TBP=216,TBP2=516))

Subject ID: 1 Events: 88 Covariates: TBP, TBP2

Let's simulate for plasma concentration with the specific observation time points after Oral administration of NT before, during and after treatment with PB.

Random.seed!(123) sim_sub1 = simobs(pk_21, sub1, param, obstimes=0:1:800) df1 = DataFrame(sim_sub1)

Use the dataframe for plotting

df1_dv = filter(x -> x.time in [0,168,171,172,175,216,360,361,363,365,368,384,432,504,505,507,509,552,600,696,697,699,701,704], df1) @df df1 plot(:time, :cp, title= "Plasma Concentration vs Time", label="Pred - Conc", xlabel="Time (hr)", ylabel="Concentration (nM)", linewidth=3, xlims=(100,800), ylims=(0,120), xticks=[0,100,200,300,400,500,600,700,800], yticks=[0,20,40,60,80,100,120]) @df df1_dv scatter!(:time, :cp, label="Obs - Conc")