{
  "id": "pk_pegasparaginase_modified_wurthwein",
  "ode_code": "\
    dAdt[0] = - (CLi/Vi + Qi/Vi) * A[0] \
    dAdt[1] = + (Qi/Vi)*A[0] - (CLi/Vi + Qi/Vi)*A[1] \
    dAdt[2] = + (Qi/Vi)*A[1] - (CLi/Vi + Qi/Vi)*A[2] \
    dAdt[3] = + (Qi/Vi)*A[2] - (CLi/Vi + Qi/Vi)*A[3] \
    dAdt[4] = + (Qi/Vi)*A[3] - (CLi/Vi + Qi/Vi)*A[4] \
    dAdt[5] = + (Qi/Vi)*A[4] - (CLi/Vi + Qi/Vi)*A[5] \
    dAdt[6] = + (Qi/Vi)*A[5] - (CLi/Vi + Qi/Vi)*A[6] \
    dAdt[7] = + (Qi/Vi)*A[6] - (CLi/Vi + Qi/Vi)*A[7] \
    dAdt[8] = + (Qi/Vi)*A[7] - (CLi/Vi + Qi/Vi)*A[8] \
    dAdt[9] = + (Qi/Vi)*A[8] - (CLi/Vi + Qi/Vi)*A[9] \
    dAdt[10] = + (Qi/Vi)*A[9] - (CLi/Vi + Qi/Vi)*A[10] \
    dAdt[11] = + (Qi/Vi)*A[10] - (CLi/Vi + Qi/Vi)*A[11] \
    dAdt[12] = + (Qi/Vi)*A[11] - (CLi/Vi + Qi/Vi)*A[12] \
    dAdt[13] = + (Qi/Vi)*A[12] - (CLi/Vi + Qi/Vi)*A[13] \
    CONC = (A[0] + A[1] + A[2] + A[3] + A[4]+ A[5] + A[6] + A[7] + A[8] + A[9] + A[10] + A[11] + A[12] + A[13])/Vi \
    dAdt[14] = CONC \
  ",
  "pk_code": "\
   BSA = pow(((HT*WT)/3600),0.5) \
   if(AGE<=8) {CLAGE = 1 ;} \
   if(AGE>8) {CLAGE = 1 + 0.021*(AGE - 8.0) ;} \
   CLSEX = 1.0 * pow(1-0.077, 1-SEX) \
   RELCLCOV= CLAGE * CLSEX \
   CLi     = (CL/24) * (1+1.44345*(BSA-0.79)) * RELCLCOV \
   Vi      = V  * (1+1.56498*(BSA-0.79)) \
   Qi      = (Q/24)  * (1+1.44345*(BSA-0.79)) \
  ",
  "n_comp": 15,
  "obs":  { "variable": "CONC" },
  "dose": { "cmt": 1, "bioav": 1 },
  "covariates": [ "AGE","SEX","HT","WT"],
  "variables": [ "CLi","Vi","Qi","CONC","RELCLCOV","BSA","CLAGE","CLSEX"],
  "parameters" : {
    "CL": 0.0517535,
    "V" : 1.74477,
    "Q" : 1.09894
  },
  "fixed": ["Q","V"],
  "units": {
    "CL": "L/d",
    "V": "L/kg",
    "Q": "L/d"
  },
  "iiv": {
    "CL": 0.8083081
  },
  "omega_matrix": [0.653362],
  "iov": null,
  "ruv": {
    "prop": 0.221777,
    "add": 0.102318
    },
 "misc": {
    "model_type": "custom",
    "linearity": "linear",
    "timevarying_parameter": false,
    "init_parameter": false
  },
  "references": [
    {
      "ref": "Würthwein et al. European Journal of Drug Metabolism and Pharmacokinetics. 2021",
      "url": "https://link.springer.com/article/10.1007/s13318-021-00670-8#Sec181"
    }
  ],
  "comments": [
   "Utilizing updated/simplified model from 2021 publication.",
   "Removed IOV and specific occasion effects on CL & V, which were specific to the trial and not generalizable to real-world application.",
   "Re-estimated IIV on CLP, which was much larger than original publication. Larger IIV is in line with literature and clinical understanding about high variability in peg-asparaginase PK."
  ],
  "version": "0.1.4"
}
