Absorption Models

Authors

Vijay Ivaturi

Jose Storopoli

using Random
using Pumas
using PumasUtilities
using CairoMakie

Random.seed!(1234)  # Set random seed for reproducibility

1 Introduction

Absorption modeling is an integral part of pharmacokinetic modeling for drugs delivered by any route of administration other than intravenous (IV) (e.g. oral, subcutaneous, intramuscular, transdermal, nasal, etc.). In the simplest case, drugs administered orally may undergo first-order absorption, whereby the absorption from the depot compartment (i.e. gut) to the central compartment (i.e. plasma) is a first-order process. However, many more complex situations arise in practice, some of which will becovered in this tutorial.

We will cover the following absorption models:

First-order
Zero-order
Parallel zero-order and first-order
Two parallel first-order processes
Weibull-type absorption
Absorption through a sequence of transit compartments (Erlang absorption)

2 Generating the Population

We begin by simulating a population of 10 subjects to use for illustration purposes in this tutorial. For simplicity, we will use a 1-compartment distribution system with additional absorption compartment(s) as required. Note that in these examples we are simulating without residual error (it could be added, but isn’t necessary here). Hence, we use the @observed block that is designed to capture post dynamics outputs.

dose1 = DosageRegimen(100; time = 0)

1×10 DataFrame

Row	time	cmt	amt	evid	ii	addl	rate	duration	ss	route
	Float64	Int64	Float64	Int8	Float64	Int64	Float64	Float64	Int8	NCA.Route
1	0.0	1	100.0	1	0.0	0	0.0	0.0	0	NullRoute

choose_covariates() = (; wt = rand(55:80), dose = 100)

choose_covariates (generic function with 1 method)

subj_with_covariates1 = map(
    i -> Subject(;
        id = i,
        events = dose1,
        covariates = choose_covariates(),
        observations = (; conc = nothing),
    ),
    1:10,
)

Population
  Subjects: 10
  Covariates: wt, dose
  Observations: conc

For a more in-depth discussion of simulating data with Pumas, please see the tutorial generating and simulation populations.

3 First-Order Absorption

Note

Note that we have written the model using differential equations, but we could equally have specified an “analytical” (closed-form) solution using this @dynamics block instead (see documentation on analytical solutions):

@dynamics Depots1Central1

Here is the Pumas code for a 1-compartment model with first-order absorption, diagonal random-effects structure, and allometric scaling on clearance and volume:

foabs = @model begin

    @param begin
        tvcl ∈ RealDomain(; lower = 0)
        tvvc ∈ RealDomain(; lower = 0)
        tvka ∈ RealDomain(; lower = 0)
        Ω ∈ PDiagDomain(3)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @covariates wt

    @pre begin
        CL = tvcl * (wt / 70)^0.75 * exp(η[1])
        Vc = tvvc * (wt / 70) * exp(η[2])
        Ka = tvka * exp(η[3])
    end

    @dynamics begin
        Depot' = -Ka * Depot
        Central' = Ka * Depot - (CL / Vc) * Central
    end

    @observed begin
        conc = @. Central / Vc
    end
end

PumasModel
  Parameters: tvcl, tvvc, tvka, Ω
  Random effects: η
  Covariates: wt
  Dynamical system variables: Depot, Central
  Dynamical system type: Matrix exponential
  Derived: 
  Observed: conc

param1 = (; tvcl = 5, tvvc = 20, tvka = 1, Ω = Diagonal([0.04, 0.04, 0.04]))
sims1 = simobs(foabs, subj_with_covariates1, param1; obstimes = 0:0.1:24)

Simulated population (Vector{<:Subject})
  Simulated subjects: 10
  Simulated variables: conc

sim_plot(
    sims1;
    observations = [:conc],
    figure = (; fontsize = 18),
    axis = (;
        xlabel = "Time (hr)",
        ylabel = "Predicted Concentration (ng/mL)",
        title = "First-order absorption",
    ),
)

4 Zero-Order Absorption

Note

Notice that there is no depot compartment, and that instead the absorption takes place in the @dosecontrol block by specifying a duration for the zero-order process. In order for this to work, we need to set the rate data item in DosageRegimen to the value -2; this is a clue to the Pumas engine that the rate should be derived from the duration and amt.

Zero-order absorption is less common than first-order absorption. It is essentially like an IV infusion, but where the duration of the infusion is an estimated parameter rather than a known quantity. Here is the Pumas code for the same 1-compartment model but with zero-order absorption:

zoabs = @model begin
    @param begin
        tvcl ∈ RealDomain(; lower = 0)
        tvvc ∈ RealDomain(; lower = 0)
        tvdur ∈ RealDomain(; lower = 0)
        Ω ∈ PDiagDomain(3)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @covariates wt

    @pre begin
        CL = tvcl * (wt / 70)^0.75 * exp(η[1])
        Vc = tvvc * (wt / 70) * exp(η[2])
    end

    @dosecontrol begin
        duration = (; Central = tvdur * exp(η[3]))
    end

    @dynamics begin
        Central' = -(CL / Vc) * Central
    end

    @observed begin
        conc = @. Central / Vc
    end

end

PumasModel
  Parameters: tvcl, tvvc, tvdur, Ω
  Random effects: η
  Covariates: wt
  Dynamical system variables: Central
  Dynamical system type: Matrix exponential
  Derived: 
  Observed: conc

param2 = (; tvcl = 0.792, tvvc = 13.7, tvdur = 5.0, Ω = Diagonal([0.04, 0.04, 0.04]))
dose2 = DosageRegimen(
    100;
    time = 0,
    rate = -2, # Note: rate must be -2 for duration modeling
)
subj_with_covariates2 = map(
    i -> Subject(;
        id = i,
        events = dose2,
        covariates = choose_covariates(),
        observations = (; conc = nothing),
    ),
    1:10,
)
sims2 = simobs(zoabs, subj_with_covariates2, param2; obstimes = 0:0.1:48)

Simulated population (Vector{<:Subject})
  Simulated subjects: 10
  Simulated variables: conc

sim_plot(
    zoabs,
    sims2;
    observations = [:conc],
    figure = (; fontsize = 18),
    axis = (;
        xlabel = "Time (hr)",
        ylabel = "Predicted Concentration (ng/mL)",
        title = "Zero-order absorption",
    ),
)

5 Parallel Zero-Order and First-Order Absorption

This is a more complex absorption model, with both a zero-order process and a first-order process operating simultaneously. Essentially, the total dose is split into two parts, one of which undergoes first-order absorption, and the other zero-order absorption (how this splitting is typically accomplished from a technical perspective is to treat each actual dose as two virtual doses with different bioavailable fractions, as in the example below). Furthermore, we will assume that the first-order process is subject to a lag (i.e., the absorption begins after a certain time delay, which is a model parameter).

zofo_paral_abs = @model begin

    @param begin
        tvcl ∈ RealDomain(; lower = 0)
        tvvc ∈ RealDomain(; lower = 0)
        tvka ∈ RealDomain(; lower = 0)
        tvdur ∈ RealDomain(; lower = 0)
        tvbio ∈ RealDomain(; lower = 0)
        tvlag ∈ RealDomain(; lower = 0)
        Ω ∈ PDiagDomain(2)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @covariates wt

    @pre begin
        CL = tvcl * (wt / 70)^0.75 * exp(η[1])
        Vc = tvvc * (wt / 70) * exp(η[2])
        Ka = tvka
    end

    @dosecontrol begin
        duration = (; Central = tvdur)
        bioav = (; Depot = tvbio, Central = 1 - tvbio)
        lags = (; Depot = tvlag)
    end

    @dynamics begin
        Depot' = -Ka * Depot
        Central' = Ka * Depot - (CL / Vc) * Central
    end

    @observed begin
        conc = @. Central / Vc
    end

end

PumasModel
  Parameters: tvcl, tvvc, tvka, tvdur, tvbio, tvlag, Ω
  Random effects: η
  Covariates: wt
  Dynamical system variables: Depot, Central
  Dynamical system type: Matrix exponential
  Derived: 
  Observed: conc

Note

With these parameter values, the first-order process starts 1 hour after administration, while the zero-order process lasts 2 hours. Hence, there is one hour where they overlap.

param3 = (;
    tvcl = 5,
    tvvc = 50,
    tvka = 1.2,
    tvdur = 2,
    tvbio = 0.5,
    tvlag = 1,
    Ω = Diagonal([0.04, 0.04]),
)
dose_zo = DosageRegimen(
    100;
    time = 0,
    cmt = 2,
    rate = -2, # Note: rate must be -2 for duration modeling
    evid = 1,
)
dose_fo = DosageRegimen(100; time = 0, cmt = 1, rate = 0, evid = 1)
dose3 = DosageRegimen(dose_fo, dose_zo)  # Actual dose is made up of 2 virtual doses
subj_with_covariates3 = map(
    i -> Subject(;
        id = i,
        events = dose3,
        covariates = choose_covariates(),
        observations = (; conc = nothing),
    ),
    1:10,
)
sims3 = simobs(zofo_paral_abs, subj_with_covariates3, param3; obstimes = 0:0.1:24)

Simulated population (Vector{<:Subject})
  Simulated subjects: 10
  Simulated variables: conc

sim_plot(
    sims3;
    observations = [:conc],
    figure = (; fontsize = 18),
    axis = (;
        xlabel = "Time (hr)",
        ylabel = "Predicted Concentration (ng/mL)",
        title = "Zero- and first-order parallel absorption",
    ),
)

6 Absorption by Two Parallel First-Order Processes

This is similar to the example above, except that both parallel processes are first-order rather than one being zero-order. We will refer to the two processes as “immediate release” (IR) and “slow release” (SR); only the SR process is subject to a lag. The Pumas code is as follows:

two_parallel_foabs = @model begin

    @param begin
        tvcl ∈ RealDomain(; lower = 0)
        tvvc ∈ RealDomain(; lower = 0)
        tvka1 ∈ RealDomain(; lower = 0)
        tvka2 ∈ RealDomain(; lower = 0)
        tvlag ∈ RealDomain(; lower = 0)
        tvbio ∈ RealDomain(; lower = 0)
        Ω ∈ PDiagDomain(6)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @covariates wt

    @pre begin
        CL = tvcl * (wt / 70)^0.75 * exp(η[1])
        Vc = tvvc * (wt / 70) * exp(η[2])
        Ka1 = tvka1 * exp(η[3])
        Ka2 = tvka2 * exp(η[4])
    end

    @dosecontrol begin
        lags = (; SR = tvlag * exp(η[5]))
        bioav = (; IR = tvbio * exp(η[6]), SR = (1 - tvbio) * exp(η[6]))
    end

    @dynamics begin
        IR' = -Ka1 * IR
        SR' = -Ka2 * SR
        Central' = Ka1 * IR + Ka2 * SR - Central * CL / Vc
    end

    @observed begin
        conc = @. Central / Vc
    end

end

PumasModel
  Parameters: tvcl, tvvc, tvka1, tvka2, tvlag, tvbio, Ω
  Random effects: η
  Covariates: wt
  Dynamical system variables: IR, SR, Central
  Dynamical system type: Matrix exponential
  Derived: 
  Observed: conc

param4 = (;
    tvcl = 5,
    tvvc = 50,
    tvka1 = 0.8,
    tvka2 = 0.6,
    tvlag = 5,
    tvbio = 0.5,
    Ω = Diagonal([0.04, 0.04, 0.36, 0.36, 0.04, 0.04]),
)
dose_fo1 = DosageRegimen(100; cmt = 1, time = 0)
dose_fo2 = DosageRegimen(100; cmt = 2, time = 0)
dose4 = DosageRegimen(dose_fo1, dose_fo2)  # Actual dose is made up of 2 virtual doses
subj_with_covariates4 = map(
    i -> Subject(;
        id = i,
        events = dose4,
        covariates = choose_covariates(),
        observations = (; conc = nothing),
    ),
    1:10,
)
sims4 = simobs(two_parallel_foabs, subj_with_covariates4, param4; obstimes = 0:0.1:48)

Simulated population (Vector{<:Subject})
  Simulated subjects: 10
  Simulated variables: conc

sim_plot(
    sims4,
    observations = [:conc],
    figure = (; fontsize = 18),
    axis = (;
        xlabel = "Time (hr)",
        ylabel = "Predicted Concentration (ng/mL)",
        title = "Two Parallel first-order absorption",
    ),
)

7 Weibull-Type Absorption

Yet other situations call for an absorption process that varies over time. One such model is this Weibull-type model, whereby the absorption is by a first-order process, but with a rate constant that is continuously changing over time according to a Weibull function (i.e., the CDF of a Weibull distribution). Here is the Pumas code for this model:

weibullabs = @model begin

    @param begin
        tvcl ∈ RealDomain(; lower = 0)
        tvvc ∈ RealDomain(; lower = 0)
        tvka ∈ RealDomain(; lower = 0)
        tvγ ∈ RealDomain(; lower = 0)
        Ω ∈ PDiagDomain(4)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @covariates wt

    @pre begin
        CL = tvcl * (wt / 70)^0.75 * exp(η[1])
        Vc = tvvc * (wt / 70) * exp(η[2])
        Ka∞ = tvka * exp(η[3])         # Maximum Ka as t → ∞
        γ = tvγ * exp(η[4])            # Controls the steepness of the Ka curve
        Kaᵗ = 1 - exp(-(Ka∞ * t)^γ)    # Weibull function
    end

    @dynamics begin
        Depot' = -Kaᵗ * Depot
        Central' = Kaᵗ * Depot - (CL / Vc) * Central
    end

    @derived begin
        conc = @. Central / Vc
    end

end

PumasModel
  Parameters: tvcl, tvvc, tvka, tvγ, Ω
  Random effects: η
  Covariates: wt
  Dynamical system variables: Depot, Central
  Dynamical system type: Nonlinear ODE
  Derived: conc
  Observed: conc

param5 =
    (; tvcl = 5, tvvc = 50, tvka = 0.4, tvγ = 4, Ω = Diagonal([0.04, 0.04, 0.36, 0.04]))
dose5 = DosageRegimen(100; cmt = 1, time = 0)
subj_with_covariates5 = map(
    i -> Subject(;
        id = i,
        events = dose5,
        covariates = choose_covariates(),
        observations = (; conc = nothing),
    ),
    1:10,
)
sims5 = simobs(weibullabs, subj_with_covariates5, param5, obstimes = 0:0.1:24)

Simulated population (Vector{<:Subject})
  Simulated subjects: 10
  Simulated variables: conc

sim_plot(
    sims5,
    observations = [:conc],
    figure = (; fontsize = 18),
    axis = (;
        xlabel = "Time (hr)",
        ylabel = "Predicted Concentration (ng/mL)",
        title = "Weibull absorption",
    ),
)

8 Erlang Absorption

The Erlang absorption model is based on the concept of transit compartments. The Erlang distribution is a special case of the Gamma distribution that arises as the sum of \(k\) independent exponential distributions. This is exactly the distribution of the transit time taken by a particle passing through a sequence of \(k\) compartments where the transition from one compartment to the next is governed by first-order processes with a common rate constant \(K_{tr}\). In Pumas, this model can be written with the following code (we assume \(N = 5\) transit compartments):

erlangabs = @model begin

    @param begin
        tvcl ∈ RealDomain(; lower = 0)
        tvvc ∈ RealDomain(; lower = 0)
        tvktr ∈ RealDomain(; lower = 0)
        Ω ∈ PSDDomain(3)
    end

    @random begin
        η ~ MvNormal(Ω)
    end

    @covariates wt

    @pre begin
        CL = tvcl * (wt / 70)^0.75 * exp(η[1])
        Vc = tvvc * (wt / 70) * exp(η[2])
        Ktr = tvktr * exp(η[3])
    end

    @dynamics begin
        Depot' = -Ktr * Depot
        Transit1' = Ktr * Depot - Ktr * Transit1
        Transit2' = Ktr * Transit1 - Ktr * Transit2
        Transit3' = Ktr * Transit2 - Ktr * Transit3
        Transit4' = Ktr * Transit3 - Ktr * Transit4
        Transit5' = Ktr * Transit4 - Ktr * Transit5
        Central' = Ktr * Transit5 - (CL / Vc) * Central
    end

    @observed begin
        conc = @. Central / Vc
    end

end

PumasModel
  Parameters: tvcl, tvvc, tvktr, Ω
  Random effects: η
  Covariates: wt
  Dynamical system variables: Depot, Transit1, Transit2, Transit3, Transit4, Transit5, Central
  Dynamical system type: Matrix exponential
  Derived: 
  Observed: conc

param6 = (; tvcl = 7, tvvc = 32, tvktr = 2.6, Ω = Diagonal([0.09, 0.22, 0.10]))
dose6 = DosageRegimen(100; cmt = 1, time = 0)
subj_with_covariates6 = map(
    i -> Subject(;
        id = i,
        events = dose6,
        covariates = choose_covariates(),
        observations = (; conc = nothing),
    ),
    1:10,
)
sims6 = simobs(erlangabs, subj_with_covariates6, param6; obstimes = 0:1:24)

Simulated population (Vector{<:Subject})
  Simulated subjects: 10
  Simulated variables: conc

sim_plot(
    sims6,
    observations = [:conc],
    figure = (; fontsize = 18),
    axis = (;
        xlabel = "Time (hr)",
        ylabel = "Predicted Concentration (ng/mL)",
        title = "Erlang absorption",
    ),
)

9 Conclusion

We have seen in this tutorial some examples of how to implement various absorption models that are commonly employed in pharmacokinetic modeling using Pumas. The powerful Pumas modeling language framework makes it relatively straightforward to implement these and other complex PK and PKPD models for modeling and simulation purposes.

This concludes our tutorial on basic absorption models with Pumas. Thanks for reading, and please be sure to check out our other tutorials as well.

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