Structural model - Two compartment linear elimination with zero order absorption

Route of administration - Three consecutive constant rate IV infusion

Dosage Regimen - 1st dose:- 26.9 mcg/kg over 15min, 2nd dose:- 139 mcg/kg from 15min to 8hr, 3rd dose:- 138.95 mcg/kg between 8hr to 24hr

Number of Subjects - 1

In this model you will learn how to build a two compartment model and simulate for a single subject.

Call the "necessary" libraries to get start.

using Random using Pumas using PumasUtilities using CairoMakie

In this two compartment model we administer three consecutive IV infusion for a single subject and we assess the disposition of drug and fitting the model to the observed data.

pk_39 = @model begin @metadata begin desc = "Two Compartment Model" timeu = u"hr" end @param begin "Clearance (L/kg/hr)" tvcl ∈ RealDomain(lower=0) "Volume of Central Compartment (L/kg)" tvvc ∈ RealDomain(lower=0) "Volume of Peripheral Compartment (L/kg)" tvvp ∈ RealDomain(lower=0) "Intercompartmental clearance (L/kg/hr)" tvq ∈ RealDomain(lower=0) Ω ∈ PDiagDomain(4) "Proportional RUV" σ²_prop ∈ RealDomain(lower=0) end @random begin η ~ MvNormal(Ω) end @pre begin CL = tvcl * exp(η[1]) Vc = tvvc * exp(η[2]) Vp = tvvp * exp(η[3]) Q = tvq * exp(η[4]) end @dynamics begin Central' = (Q/Vp)*Peripheral - (Q/Vc)*Central -(CL/Vc)*Central Peripheral' = -(Q/Vp)*Peripheral + (Q/Vc)*Central end @derived begin cp = @. Central/Vc """ Observed Concentration (ug/L) """ dv ~ @. Normal(cp, sqrt(cp^2*σ²_prop)) end end

PumasModel Parameters: tvcl, tvvc, tvvp, tvq, Ω, σ²_prop Random effects: η Covariates: Dynamical variables: Central, Peripheral Derived: cp, dv Observed: cp, dv

Parameters provided for simulation. `tv`

represents the typical value for parameters.

$Cl$ - Clearance (L/kg/hr)

$Vc$ - Volume of Central Compartment (L/kg)

$Vp$ - Volume of Peripheral Compartment (L/kg)

$Q$ - Intercompartmental clearance (L/kg/hr)

$Ω$ - Between Subject Variability

$σ$ - Residual error

param = (tvcl = 0.417793, tvvc = 0.320672, tvvp = 2.12265, tvq = 0.903188, Ω = Diagonal([0.0,0.0,0.0,0.0]), σ²_prop = 0.005)

(tvcl = 0.417793, tvvc = 0.320672, tvvp = 2.12265, tvq = 0.903188, 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)

Single subject receiving three consecutive IV infusion

1st dose:

**26.9 mcg/kg over 15min**2nd dose:

**139 mcg/kg from 15min to 8hr**3rd dose:

**138.95 mcg/kg between 8hr to 24hr**

ev1 = DosageRegimen([26.9,139,138.95], time=[0,0.25,8], cmt=1, duration=[0.25,7.85,16]) sub1 = Subject(id=1, events=ev1)

Subject ID: 1 Events: 6

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

Random.seed!(123) sim_sub1 = simobs(pk_39, sub1, param, obstimes=0:0.01:60)

f1, a1, p1 = sim_plot(pk_39, [sim_sub1], observations = :cp, color = :redsblues, linewidth = 4, axis = ( xlabel = "Time (hr)", ylabel = "PK39 Concentrations (μg/L)", xticks = 0:10:60)) f1