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Anakinra exposure and conditional CRP turnover

Apparent subcutaneous anakinra exposure inhibits empirical CRP production. Fixed responder and waning-sensitivity groups distinguish sustained suppression from rebound under a constant or PK-derived concentration driver.

Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes ↗
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10 kg, 2 mg/kg/day apparent SC

How does bodyweight-projected apparent SC exposure change under a fixed daily administered dose?

0–720 h

Study

10 kg, 2 mg/kg/day apparent SC

How does bodyweight-projected apparent SC exposure change under a fixed daily administered dose?

Readouts

PK derived anakinra concentration· mg/L
Apparent plasma PK concentration central/(V/F); zero in constant-driver cases without SC dosing.
Conditional crp concentration· mg/L
Fixed group baseline times normalized CRP response; empirical biomarker output, not patient prediction.

Study purpose

  • How does bodyweight-projected apparent SC exposure change under a fixed daily administered dose?

Interpretation limits

  • Conditional fixed-effect exploration only; no clinical dose recommendations, individual patient inference, original fit or population prediction.
  • Clearance and volume are apparent CL/F and V/F. Unknown physical bioavailability is not identified by the unit dose multiplier or apparent amount ledger.
  • High-baseline and lower-baseline contexts are fixed conditional groups, not estimated mixture probabilities. Remaining effect sensitivity declines in the waning context; it is not resistance prevalence.
  • Imposed-concentration contexts drive CRP externally. They do not produce PK concentration or PK exposure without administrations. Clearance and absorption controls are relevant to SC contexts; imposed concentration is relevant only to imposed-driver contexts.
  • Clearance bounds span retained bodyweight-projected values, but changing clearance alone is not a bodyweight projection. Absorption and turnover ranges are authored 0.5–1.5× default perturbations. Sensitivity-loss bounds span zero to 1.5× the source RESI rate. The imposed-concentration interval spans the source Figure 3 settings and zero. None is a clinical or uncertainty interval.
  • Bodyweight is resolved into each starting configuration. Dose amounts and volume stay fixed when clearance is edited; choosing a different configuration changes the jointly authored context.
  • The source between-occasion volume variability, patient observations, BLQ/log10 likelihood, mixed-effects fit and prediction intervals are not reproduced.
  • No complete source figure panel is reproduced. Rounded Table 1 versus prose coefficients, literal Table 2 uncertainty entries and the reported group proportions remain source limitations.
  • Changing the start resets the supplied initial states; earlier administrations are not reconstructed. Dose-event observations retain their declared pre/post side.
  • Long coupled histories are mechanistic diagnostics and do not establish observed long-term clinical behavior.
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Edit inputs

PK clearance

Apparent clearance CL/F, projected from source bodyweight; physical bioavailability unknown. Exploratory control; interpretation depends on the selected context.

L/h
2.5003 → —
SC absorption

First-order SC absorption rate. Exploratory control; interpretation depends on the selected context.

1/h
0.38 → —
CRP turnover

Empirical CRP turnover rate, converted from day to hour. Exploratory control; interpretation depends on the selected context.

1/h
0.00175 → —
Effect sensitivity

Decay rate of remaining drug-effect sensitivity; zero for RESP and 0.0048/day for RESI. Exploratory control; interpretation depends on the selected context.

1/h
0 → —
External concentration driver

Externally imposed PD concentration only when mode is one. Exploratory control; interpretation depends on the selected context.

mg/L
0 → —
Simulation time
h
h
720 → 168

Time between reported samples.

h
6 → 1

2 changes · Variation 1

Continue in the background and keep the result.

Biology

Apparent subcutaneous anakinra exposure inhibits empirical CRP production. Fixed responder and waning-sensitivity groups distinguish sustained suppression from rebound under a constant or PK-derived concentration driver.

Apparent subcutaneous anakinra exposure inhibits empirical CRP production. Fixed responder and waning-sensitivity groups distinguish sustained suppression from rebound under a constant or PK-derived concentration driver.
States & equation dependencies
What are the modeled states and equation-linked processes?Representative technical topology with 6 selected states: Administration-site amount, Central-compartment amount, Response, Resistance, Exposure (AUC), Eliminated. Displayed equation-linked dependencies: from Administration-site amount to Central-compartment amount; from Central-compartment amount to Response; from Resistance to Response; from Central-compartment amount to Exposure (AUC); from Central-compartment amount to Eliminated. Displayed model or scenario entry points: Administered input enters Administration-site amount. There are no separately labeled equation controls.TECHNICAL TOPOLOGYWhat are the modeled states and equation-linked processes?Selected equation-linked states · model time unit: hAdministered inputAdministration-site amountmgCentral-compartment amountmgResponse1Resistance1Exposure (AUC)mg.h/LEliminatedmg
Teal arrows show relationships between modeled states and do not always represent material transfer. Peach arrows mark administered or scenario-defined entry points.

Assumptions & evidence

Assumptions & limitations

  • Conditional fixed-effect exploration only; no clinical dose recommendations, individual patient inference, original fit or population prediction.
  • Clearance and volume are apparent CL/F and V/F. Unknown physical bioavailability is not identified by the unit dose multiplier or apparent amount ledger.
  • High-baseline and lower-baseline contexts are fixed conditional groups, not estimated mixture probabilities. Remaining effect sensitivity declines in the waning context; it is not resistance prevalence.
  • Imposed-concentration contexts drive CRP externally. They do not produce PK concentration or PK exposure without administrations. Clearance and absorption controls are relevant to SC contexts; imposed concentration is relevant only to imposed-driver contexts.
  • Clearance bounds span retained bodyweight-projected values, but changing clearance alone is not a bodyweight projection. Absorption and turnover ranges are authored 0.5–1.5× default perturbations. Sensitivity-loss bounds span zero to 1.5× the source RESI rate. The imposed-concentration interval spans the source Figure 3 settings and zero. None is a clinical or uncertainty interval.
  • Bodyweight is resolved into each starting configuration. Dose amounts and volume stay fixed when clearance is edited; choosing a different configuration changes the jointly authored context.
  • The source between-occasion volume variability, patient observations, BLQ/log10 likelihood, mixed-effects fit and prediction intervals are not reproduced.
  • No complete source figure panel is reproduced. Rounded Table 1 versus prose coefficients, literal Table 2 uncertainty entries and the reported group proportions remain source limitations.
  • Changing the start resets the supplied initial states; earlier administrations are not reconstructed. Dose-event observations retain their declared pre/post side.
  • Long coupled histories are mechanistic diagnostics and do not establish observed long-term clinical behavior.

Parameter origins

  • Released executable model definition; exact publication locator not reported

Validation & references

One or more implementation checks are available; this is not a claim of full model reproduction.

Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes ↗

Available reference curves can be added to the plot when their scenario, readout, time and units match.

Model details

9 parameters · 6 states · 6 equations · 9 derived outputs

Classification & API access
Therapeutic
anakinra
Modality
Other biologic or therapeutic modality
Target
IL1R1
Disease / scope
systemic juvenile idiopathic arthritis, autoinflammatory syndromes
ParameterDefaultUnitDescription
Baselinebaseline141mg/LFixed group baseline CRP, not fitted individual baseline. Envelope covers frozen private cases, not public scan or fitting bounds.
C50c500.03mg/LConcentration for half initial inhibition of CRP production. Envelope covers frozen private cases, not public scan or fitting bounds.
Systemic clearancecl6.24L/hApparent clearance CL/F, projected from source bodyweight; physical bioavailability unknown. Exploratory control; interpretation depends on the selected context.
Imposed PD concentrationconstant_c0mg/LExternally imposed PD concentration only when mode is one. Exploratory control; interpretation depends on the selected context.
Absorption rate constantka0.381/hFirst-order SC absorption rate. Exploratory control; interpretation depends on the selected context.
Loss of effect sensitivitykresi01/hDecay rate of remaining drug-effect sensitivity; zero for RESP and 0.0048/day for RESI. Exploratory control; interpretation depends on the selected context.
Crp turnover ratektr0.001751/hEmpirical CRP turnover rate, converted from day to hour. Exploratory control; interpretation depends on the selected context.
Modemode01Fixed diagnostic switch: zero uses PK-derived concentration, one supplies constant_c. Intermediate mixtures are unqualified. Envelope covers frozen private cases, not public scan or fitting bounds.
Central distribution volumevc65.2LApparent volume V/F, projected from source bodyweight; physical distribution volume unidentified. Envelope covers frozen private cases, not public scan or fitting bounds.

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