pbpk regional absorption¶

The derivation of a regional absorption profile with the model from a release study: release_auc_ratios (the AUC of a solution released in a segment relative to the oral solution), derive_regional_absorption (the factors of a RegionalAbsorption which give the reported ratios) and regional_key, see Intestine and routes.

Derive a regional absorption profile with the model from a release study.

A regional absorption study releases a solution of the drug in a segment of the intestine (an intubation, a remote-controlled capsule) and reports its exposure relative to an oral solution, e.g. the AUC of apixaban released in the distal small bowel 0.40 and in the ascending colon 0.16 of the oral solution (Byon 2018). The factors of a RegionalAbsorption profile which give these ratios depend on the rest of the absorption of the model (ka, fabs, an efflux, the first pass), so they are derived with the model:

release_auc_ratios simulates the oral solution (SOLDOSE_<s>) and the same dose put dissolved into the lumen of each release segment (GU__Clumen_<seg>_<s>) and gives the AUC of the arm vein relative to the oral solution;
derive_regional_absorption finds the factors for which the ratios are the reported ones: one factor per release segment, the factor of the profile which scales the absorption there (regional_key: the segment itself in the small intestine, the group colon in the large intestine), each the root of its ratio (brentq) with the others fixed, in turns until no factor moves (a release reaches the other regions little, so a few turns converge).

Because the ratios depend on the fitted absorption, a model derives the factors on its adopted fit, writes them into its profile (a Value with the source of the study) and fits again from the adopted fit, until the factors derived on the fit are those of the model. The model must have the factors (its profile names them, e.g. with a first guess) and an oral solution of the substance.

DAY `module-attribute` ¶

DAY = 24 * 60.0

A day [min].

regional_key ¶

regional_key(segment)

The key of the profile whose factor scales the absorption of a release segment.

Parameters:

Name	Type	Description	Default
`segment`	`str`	the token of an absorbing segment (`du` to `rec`).	required

Returns:

Type	Description
`str`	The segment itself in the small intestine, the group `colon` in the
`str`	large intestine (caecum to rectum).

Raises:

Type	Description
`ValueError`	for the stomach or an unknown token.

release_auc_ratios ¶

release_auc_ratios(
    r,
    substance,
    segments,
    dose,
    *,
    factors=None,
    changes=None,
    end=14 * DAY,
    points=20161,
    observable=None,
)

Get the AUC of a solution released in each segment relative to the oral solution.

Every simulation starts from the initial values of the model in the condition of the study (changes, set as initial values) with the factors set; the oral solution is the dose state SOLDOSE_<s>, a release the dose dissolved in the lumen of the segment (dose/Mr/Vlumen). The AUC is the trapezoid of observable over points equidistant times from 0 to end. Afterwards the condition is taken back and every value of r is reset to its initial value (reset of all values): a value set on r before the call is kept only if it was set as an initial value.

Parameters:

Name	Type	Description	Default
`r`	`RoadRunner`	the model, a roadrunner of the flat model with the tolerances of the derivation (e.g. absolute 1e-14, relative 1e-10).	required
`substance`	`str`	the substance id.	required
`segments`	`Sequence[str]`	the release segments (`ile2`, `asc`).	required
`dose`	`float`	the dose [mg].	required
`factors`	`Mapping[str, float] \| None`	the factors of the profile by key (`regional_key`), those of the model if `None`.	`None`
`changes`	`Mapping[str, float] \| None`	the condition of the study, initial values by id (`FED`, `BW`, an activity); none if `None`.	`None`
`end`	`float`	the end of the simulations [min], long enough for the AUC.	`14 * DAY`
`points`	`int`	the number of time points.	`20161`
`observable`	`str \| None`	the id whose AUC is compared, the arm vein `Carm_<s>` by default.	`None`

Returns:

Type	Description
`dict[str, float]`	The ratio by release segment.

Raises:

Type	Description
`ValueError`	for a segment which does not absorb, or a model without the oral solution, a lumen, a factor or a changed id.

derive_regional_absorption ¶

derive_regional_absorption(
    r,
    substance,
    targets,
    dose,
    *,
    changes=None,
    bounds=(0.0001, 10.0),
    xtol=1e-06,
    max_turns=20,
    end=14 * DAY,
    points=20161,
    observable=None,
)

Derive the factors of a profile which give the ratios of a release study.

One factor per release segment (regional_key: the segment in the small intestine, colon in the large one, so two release segments of the large intestine are refused), each the root of the ratio of its segment within bounds with the other factors fixed, in the order of targets and in turns, starting from the factors of the model, until no factor moves by more than xtol. Afterwards r is reset as by release_auc_ratios: the factors of the model, not the derived ones.

Parameters:

Name	Type	Description	Default
`r`	`RoadRunner`	the model, see `release_auc_ratios`.	required
`substance`	`str`	the substance id.	required
`targets`	`Mapping[str, float]`	the reported AUC of the release relative to the oral solution by release segment (`{"ile2": 0.40, "asc": 0.16}`).	required
`dose`	`float`	the dose of the study [mg].	required
`changes`	`Mapping[str, float] \| None`	the condition of the study, see `release_auc_ratios`.	`None`
`bounds`	`tuple[float, float]`	the bracket of every factor.	`(0.0001, 10.0)`
`xtol`	`float`	the tolerance of a factor.	`1e-06`
`max_turns`	`int`	the most turns over the factors.	`20`
`end`	`float`	see `release_auc_ratios`.	`14 * DAY`
`points`	`int`	see `release_auc_ratios`.	`20161`
`observable`	`str \| None`	see `release_auc_ratios`.	`None`

Returns:

Type	Description
`dict[str, float]`	The factors by key of the profile (`{"ile2": 0.149, "colon": 0.0567}`).

Raises:

Type	Description
`ValueError`	for two release segments of one factor, a ratio which no factor within `bounds` gives, or a model without what the derivation needs.
`RuntimeError`	if the factors do not converge in `max_turns` turns.

pbpk regional absorption¶

DAY module-attribute ¶

regional_key ¶

release_auc_ratios ¶

derive_regional_absorption ¶

DAY `module-attribute` ¶