DDMODEL00000103: Trefz_2015_metabolism_Kuvan_TurnoverKPD

  public model
Short description:
Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: A semi-mechanistically-based, nonlinear mixed-effect modeling. Assess the individual BH4 responsiveness in neonates suffering from phenylalanine hydroxylase (PAH). It is a pharmacodynamic turnover model (stimulation of loss) of Phenylalanine in blood disposition. The K-PD approach is used to describe BH4 kinetics. Mixture population approach is used to differentiate BH4 sensitive and non-sensitive patients.
PharmML (0.6.1)
  • Tetrahydrobiopterin (BH4) responsiveness in neonates with
  • F. Trefz, O. Lichtenberger, N. Blau, A. C. Muntau, F. Feillet, A. Bélanger-Quintana, F. van Spronsen, A. Munafo
  • Molecular Genetics and Metabolism, 1/2015
  • Outpatient Medical Centre for Women, Children and Adolescents, Kreiskliniken Reutlingen GmbH, 72501 Gammertingen, Marktstrasse 4, Germany Merck KGaA, Darmstadt, Germany University Children's Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
  • Neonatal loading studies with tetrahydrobiopterin (BH4) are used to detect hyperphenylalaninemia due to BH4 deficiency by evaluating decreases in blood phenylalanine (Phe) concentrations post BH4 load. BH4 responsiveness in phenylalanine hydroxylase (PAH)-deficient patients introduced a new diagnostic aspect for this test. In older children, a broad spectrum of different levels of responsiveness has been described. The primary objective of this study was to develop a pharmacodynamic model to improve the description of individual sensitivity to BH4 in the neonatal period. Secondary objectives were to evaluate BH4 responsiveness in a large number of PAH-deficient patients from a neonatal screening program and in patients with various confirmed BH4 deficiencies from the BIODEF database. Descriptive statistics in patientswith PAH deficiency with 0–24-h data available showed that 129 of 340 patients (37.9%) had a N30% decrease in Phe levels post load. Patientswith dihydropteridine reductase deficiency (n=53) could not be differentiated from BH4-responsive patients with PAH deficiency. The pharmacologic turnover model, “stimulation of loss” of Phe following BH4 load, fitted the data best. Using the model, 193 of 194 (99.5%) patients with a proven BH4 synthesis deficiency or recycling defect were classified as BH4 sensitive. Among patients with PAH deficiency, 216 of 375 (57.6%) patients showed sensitivity to BH4, albeit with a pronounced variability; PAH-deficient patientswith blood Phe b1200 ?mol/L at time 0 showed higher sensitivity than patients with blood Phe levels N1200 ?mol/L. External validation showed good correlation between the present approach, using 0–24-h blood Phe data, and the published 48-h prognostic test. Pharmacodynamic modeling of Phe levels following a BH4 loading test is sufficiently powerful to detect a wide range of responsiveness, interpretable as a measure of sensitivity to BH4. However, the clinical relevance of small responses needs to be evaluated by further studies of their relationship to long-term response to BH4 treatment.
Nadia Terranova, Kheizurane_ElMekki
Context of model development: Patient Population Selection and Bridging between Population (Pediatrics, Elderly, Obese);
Discrepancy between implemented model and original publication: The model implemented in the original publication is a mixture model, including two population: sensitive to BH4 ( the SLOP parameter is assumed lognormally distributed) and non-sensitive to BH4 (the SLOP parameter is assumed to be equal to zero).;
Long technical model description: Pharmacodynamic turnover model with stimulation of loss describing the Phenylalanine in blood (Phe) disposition. A K-PD approach was used to describe the kinetics of BH4. The model includes a mixture approaches to distinguish BH4 sensitive to non sensitive patients.;
Model compliance with original publication: No;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Pharmacodynamic model to improve the description of individual sensitivity to BH4 in neonatal period;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Metabolism;
Annotations are correct.
This model is not certified.
  • Model owner: Nadia Terranova
  • Submitted: Dec 11, 2015 4:59:26 PM
  • Last Modified: Jul 18, 2016 12:07:40 PM
Revisions
  • Version: 15 public model Download this version
    • Submitted on: Jul 18, 2016 12:07:40 PM
    • Submitted by: Nadia Terranova
    • With comment: Updated model annotations.
  • Version: 6 public model Download this version
    • Submitted on: Dec 11, 2015 4:59:26 PM
    • Submitted by: Kheizurane_ElMekki
    • With comment: Edited model metadata online.

Independent variable T

Function Definitions

combinedError2(additive,proportional,f)=(proportional2+(additive2 ×f2))

Structural Model sm

Variable definitions

dDEPOTdT=(-KDE ×DEPOT)
EFF=(SLOP ×DEPOT)
dPDdT=(KOUT-((KOUT ×(1+EFF)) ×PD))

Initial conditions

DEPOT=0
PD=1

Variability Model

Level Type

DV

 residualError

ID

 parameterVariability

Parameter Model

Parameters
POP_KOUT;  POP_KDE;  POP_SLOP;  PERR;  AERR;  OMEGA_KOUT;  OMEGA_KDE;  OMEGA_SLOP; 
ETA_KOUT∼N(0.0,OMEGA_KOUT) — ID
ETA_KDE∼N(0.0,OMEGA_KDE) — ID
ETA_SLOP∼N(0.0,OMEGA_SLOP) — ID
EPS_Y∼N(0.0,1.0) — DV
log(KOUT)=(log(POP_KOUT)+ETA_KOUT)
log(KDE)=(log(POP_KDE)+ETA_KDE)
log(SLOP)=(log(POP_SLOP)+ETA_SLOP)

Observation Model

Observation Y
Continuous / Residual Data

Parameters
Y=(PD+(combinedError2(AERR,PERR,PD) ×EPS_Y))

Estimation Steps

Estimation Step estimStep_1

Estimation parameters

Initial estimates for non-fixed parameters

  • POP_KOUT=0.0388
  • POP_KDE=0.067
  • POP_SLOP=0.205
  • PERR=0.447
  • AERR=1
  • OMEGA_KOUT=0.2
  • OMEGA_KDE=0.2
  • OMEGA_SLOP=0.2
Estimation operations
1) Estimate the population parameters
    Algorithm FOCEI

    Step Dependencies

    • estimStep_1
     
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