# Parent-metabolite + dual absorption: fitting error
**URL:** https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955
**Category:** Uncategorized
**Created:** [November 16, 2023, 11:46am UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955 "2023-11-16T11:46:05Z")
**Posts on this page:** 6
**Page:** 1
### Author:  [@chrisv](https://discourse.pumas.ai/u/chrisv)
#### Post date: [November 16, 2023, 11:46am UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955/1 "2023-11-16T11:46:05Z")
Hello. I am trying to fit a parent-metabolite model with dual absorption (ka1 and ka2). In the database I have two administrations at time t=0 with the total dose at CMT=1 (ev) and CMT=2 (ev). I get the error that the gradient is 0 and therefore the parameter is not identified:
1. First I get the error for tvlag. Then I set FIXED the tvlag parameter.
2. I get the error for tvbio. Then I set FIXED the tvio parameter.
3. I get the error for ETA(5). etc.
And so on but the model does not achieve the fit.
I will be very grateful for any possible help.
This is the code:
mymodel = @model begin
@metadata begin
desc = “Two parallel first-order absorptions - Two Compartment Model with Metabolite Compartment”
timeu = u"hr"
end
```
@param begin
"Volume of Central Compartment (L)"
tvvc ∈ RealDomain(lower=0)
"Clearance of parent drug (L/hr)"
tvclp ∈ RealDomain(lower=0)
"Inter Compartmental Clearance (L/hr)"
tvq ∈ RealDomain(lower=0)
"Volume of Peripheral Compartment (L)"
tvvp ∈ RealDomain(lower=0)
"Volume of Compartment of Metabolite (L)"
tvvm ∈ RealDomain(lower=0)
"Clearance of metabolite (L/hr)"
tvclm_M ∈ RealDomain(lower=0)
tvclm_F ∈ RealDomain(lower=0)
"Lag time (hr)"
tvlag ∈ RealDomain(lower=0)
"Absorption rate constant 1 (hr⁻¹)"
tvka1 ∈ RealDomain(lower=0)
"Absorption rate constant 2 (hr⁻¹)"
tvka2 ∈ RealDomain(lower=0)
"fraction metabolized"
tvfmet ∈ RealDomain(lower=0)
"Fraction"
tvbio ∈ RealDomain(lower=0)
# variance
Ω ∈ PDiagDomain(5)
"Proportional RUV - Plasma"
σ²_prop_cp ∈ RealDomain(lower=0.001)
"Proportional RUV - Metabolite"
σ²_prop_met ∈ RealDomain(lower=0.001)
end
@random begin
η ~ MvNormal(Ω)
end
@covariates begin
sex
end
@pre begin
tvclm = ifelse(sex == "M", tvclm_M, tvclm_F)
Vc = tvvc * exp(η[1])
Clp = tvclp * exp(η[2])
Q = tvq
Vp = tvvp
Vm = tvvm
Clm = tvclm * exp(η[3])
Ka1 = tvka1 * exp(η[4])
Ka2 = tvka2
lags = (SR = tvlag,)
bioav = (IR = tvbio*exp(η[5]), SR = 1-tvbio*exp(η[5]))
fmet = tvfmet
end
@dynamics begin
IR' = -Ka1*IR
SR' = -Ka2*SR
Central' = Ka1*IR + Ka2*SR - (1-fmet)*(Clp/Vc)*Central -(fmet)*(Clm/Vc)*Central - (Q/Vc)*Central + (Q/Vp)*Peripheral
Peripheral' = (Q/Vc)*Central - (Q/Vp)*Peripheral
Metabolite' = (fmet)*(Clp/Vc)*Central - (Clm/Vm)*Metabolite
end
@derived begin
cp = @. Central/Vc
dv_cp ~ @. Normal(cp, sqrt(cp^2*σ²_prop_cp))
met = @. Metabolite/Vm
dv_met ~ @. Normal(met, sqrt(met^2*σ²_prop_met))
end
```
end
iparams = (
tvka1 = 1,
tvka2 = 10,
tvclp = 40,
tvvc = 50,
tvq = 20,
tvvp = 120,
tvbio= 0.1,
tvlag = 0.14,
tvfmet = 0.7,
tvclm\_M = 100,
tvclm\_F = 100,
tvvm = 5,
Ω = Diagonal([0.1, 0.1, 0.1,0.1,0.0001]),
σ²\_prop\_cp = 0.1,
σ²\_prop\_met = 0.1
)
---
### Author:  [@chrisv](https://discourse.pumas.ai/u/chrisv)
#### Post date: [November 16, 2023, 12:32pm UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955/2 "2023-11-16T12:32:02Z")
1. With this fit: fit\_results = fit(model20, pop, iparams, Pumas.FOCE(),constantcoef = (tvfmet = 0.7, ))
I get this error:
ERROR: gradient is exactly zero in tvlag. This indicates that tvlag isn’t identified.
1. So I fix tvlag. With this fit: fit\_results = fit(model20, pop, iparams, Pumas.FOCE(),constantcoef = (tvfmet = 0.7,tvlag=0.14, ))
I get this error: ERROR: gradient is exactly zero in tvbio. This indicates that tvbio isn’t identified.
1. And so on parameter by parameter. I can never get the fit to work.
---
### Author:  [@parssh.mehta](https://discourse.pumas.ai/u/parssh.mehta)
#### Post date: [November 16, 2023, 9:47pm UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955/3 "2023-11-16T21:47:41Z")
> [@chrisv](#):
>
> ```auto
> lags = (SR = tvlag,)
> bioav = (IR = tvbio*exp(η[5]), SR = 1-tvbio*exp(η[5]))
>
> ```
Hi Chris,
There are a few parameters that need to come under the @dosecontrol block and not under @pre
```auto
@dosecontrol begin
lags = (SR = tvlag,)
bioav = (;IR = tvbio*exp(η[5]), SR = 1-tvbio*exp(η[5]))
end
```
This should help fix your problem. You can also read more about the @dosecontrol block [Docs-Dose Control Parameters](https://docs.pumas.ai/stable/basics/models/#@dosecontrol:-Dose-Control-Parameters)
Best,
Parssh
---
### Author:  [@chrisv](https://discourse.pumas.ai/u/chrisv)
#### Post date: [November 27, 2023, 11:42pm UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955/5 "2023-11-27T23:42:23Z")
Thank you very much for your help. I have made that change and I have also simplified the model a little, the code is now a little simpler, here it can be seen:
model24 = @model begin
```
@param begin
tvka1 ∈ RealDomain(lower=0)
tvka2 ∈ RealDomain(lower=0)
tvclp ∈ RealDomain(lower=0) #Clearance of parent drug
tvvc ∈ RealDomain(lower=0) #Volume of central compartment (parent drug)
tvq ∈ RealDomain(lower=0)
tvvp ∈ RealDomain(lower=0) #Volume of peripheral compartment (parent drug)
tvvm ∈ RealDomain(lower=0) #Volume of Compartment of Metabolite
tvclm ∈ RealDomain(lower=0)
tvlag ∈ RealDomain(lower=0)
tvbio ∈ RealDomain(lower=0)
Ω ∈ PDiagDomain(5)
σ_cp ∈ RealDomain(lower = 0.0001)
σ_met ∈ RealDomain(lower = 0.0001)
end
@random begin
η ~ MvNormal(Ω)
end
```
@pre begin
Vc = tvvc \* exp(η[1])
Clp = tvclp \* exp(η[2])
Q = tvq
Vp = tvvp
Vm = tvvm
Clm = tvclm \* exp(η[3])
Ka1 = tvka1
Ka2 = tvka2 \* exp(η[4])
end
```
@dosecontrol begin
lags = (SR = tvlag,)
bioav = (IR = tvbio*exp(η[5]), SR = 1-tvbio*exp(η[5]))
end
@dynamics begin
IR' = -Ka1*IR
SR' = -Ka2*SR
Central' = Ka1*IR + Ka2*SR - (Clp/Vc)*Central - (Q/Vc)*Central + (Q/Vp)*Peripheral
Peripheral' = (Q/Vc)*Central - (Q/Vp)*Peripheral
Metabolite' = (Clp/Vc)*Central - (Clm/Vm)*Metabolite
end
@derived begin
cp = @. Central/Vc
dv_cp ~ @. Normal(cp, σ_cp*abs(cp))
met = @. Metabolite/Vm
dv_met ~ @. Normal(met, σ_met*abs(met))
end
```
end
iparams = (
tvka1 = 0.5,
tvka2 = 10,
tvclp = 40,
tvvc = 40,
tvq = 20,
tvvp = 160,
tvbio= 0.5,
tvlag = 0.15,
tvclm = 100,
tvvm = 5,
Ω = Diagonal([0.1, 0.1, 0.1,0.1,0.1]),
σ\_cp = 0.1,
σ\_met = 0.1
)
fitted\_model = fit(model24, pop, iparams, FOCE())
But in this time I get a stranger error: “TaskedFailedException”. And no additional explanation.
---
### Author:  [@chrisv](https://discourse.pumas.ai/u/chrisv)
#### Post date: [November 28, 2023, 12:04am UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955/6 "2023-11-28T00:04:44Z")
I found the error explanation in the terminal:
nested task error: DomainError with -Inf:
Duration must be non-negative. Got a duration of -Inf and a bioavailability of -0.0036060595751163937 for compartment 2.
But the initial parameters are okay. And I understand that the differential equations are okay also.
I don’t understand why I get this domain error.
Thank you for help ! 🙂
---
### Author:  [@storopoli](https://discourse.pumas.ai/u/storopoli)
#### Post date: [November 28, 2023, 12:22pm UTC](https://discourse.pumas.ai/t/parent-metabolite-dual-absorption-fitting-error/955/7 "2023-11-28T12:22:33Z")
> [@chrisv](#):
>
> nested task error: DomainError with -Inf:
> Duration must be non-negative. Got a duration of -Inf and a bioavailability of -0.0036060595751163937 for compartment 2.
Probably because
```julia
SR = 1-tvbio*exp(η[5]))
```
can be negative if `tvbio*exp(η[5])) > 1`.
Why don’t you try a `NaivePool` fit first to see if the error is with the `η[5]` interaction?
Or even better, why not a `FOCE` fit without an eta on `tvbio`? Reduce the `Ω ∈ PDiagDomain(4)` and see if the error still happens.