Skip to content

Warfarin PKPD Real-World Validation

Dataset

  • Source: warfarin from nlmixr2data (GPL >= 3)
  • Drug: Warfarin (oral anticoagulant)
  • Subjects: 32 subjects
  • Endpoints:
  • PK: Plasma concentration (cp)
  • PD: Prothrombin complex activity (pca)

Columns

Column Description
id Subject identifier
time Time (hours)
amt Dose amount (mg)
dv Dependent variable
dvid Endpoint type (cp=concentration, pca=PD response)
evid Event ID (1=dose, 0=observation)
wt Body weight (kg)
age Age (years)
sex Sex (male/female)

Model

PK Component

  • Model: One-compartment oral (ADVAN2)
  • Parameters: | Parameter | Value | Unit | |-----------|-------|------| | Ka | 1.2 | 1/h | | CL | 3.0 | L/h | | V | 35.0 | L |

PD Component

  • Model: Indirect response turnover (inhibition of production)
  • Equation: dR/dt = Kin * (1 - Emax * C / (EC50 + C)) - Kout * R
  • Parameters: | Parameter | Value | Unit | |-----------|-------|------| | Kin | 10.0 | 1/h | | Kout | 0.5 | 1/h | | R0 | 20.0 | % activity | | Emax | 0.8 | - | | EC50 | 2.0 | mg/L |

Validation Approach

This is simulation-only validation using fixed literature-derived parameters: 1. Parse warfarin dataset with both PK and PD observations 2. Simulate coupled PKPD using NeoPKPD 3. Compute RMSE separately for PK (concentration) and PD (response) endpoints 4. Compare against expected output (deterministic replay)

Outputs

Per subject (32 subjects total): - subj_<id>.json - Coupled PKPD simulation artifact

Summary: - metrics.json - Per-subject RMSE for PK and PD endpoints

Running

# Run simulation (from repository root)
julia --project=packages/core \
  docs/examples/real_world_validation/datasets/warfarin_nlmixr2data/run.jl

# Copy to expected (first time or when regenerating)
rm -f docs/examples/real_world_validation/studies/warfarin_pkpd/expected/*.json
cp docs/examples/real_world_validation/studies/warfarin_pkpd/output/*.json \
   docs/examples/real_world_validation/studies/warfarin_pkpd/expected/

# Validate
julia --project=packages/core \
  docs/examples/real_world_validation/datasets/warfarin_nlmixr2data/validate.jl

Validation Criteria

  • Deterministic replay of all artifacts
  • Metrics matched with strict tolerance (1e-12)
  • Both PK and PD predictions validated

Key Features Demonstrated

  1. Coupled PKPD Simulation: PK drives PD through concentration-effect relationship
  2. Indirect Response Model: Turnover dynamics with inhibition of production
  3. Multi-endpoint Handling: Separate PK (cp) and PD (pca) observations
  4. Real-World Data: Actual clinical trial data structure with covariates

See Also