Search the PBPK Model Repository

  Absorption Model

• First-Order (dose and food-dependent fa – saved in different models)

  Volume of Distribution

• Full PBPK (Method 2)
• Notes: Includes a Kp scalar and Kpadipose

  Route of Elimination

• CYP3A4 (80%), CYP2C9 (10%), CYP2C19 (10%)

  Perpetrator DDI

• CYP3A4 Inhibitor

  Validation

• Two clinical studies with fasted and fed groups at varying dose levels describing single and multiple dose exposure of piperaquine were used to verify the PBPK model. All of the simulated studies were within 1.5-fold of the observed values. 
• A clinical DDI study where piperaquine was the victim of a CYP3A4-mediated DDI was accurately recovered using the PBPK model as well as a CYP3A4 perpetrator DDI with the sensitive substrate midazolam.

  Limitations

• Requires separate files for low and high dose due to dose-dependant fa​
• Cmax overprediction, likely due to formulation differences​
• Additional verification for DDIs would be ideal although studies are currently not available in literature

  Updates in V19

• Updated in vitro­ data
• LogP
• Converted model to full PBPK with Vss predicted through Method 2

  Absorption Model

• First-Order

  Volume of Distribution

• Minimal PBPK (User input Vss)

  Route of Elimination

• Renal clearance (90%); non-specific hepatic metabolism (10%)

  Perpetrator DDI

• None

  Validation

• Four clinical studies describing single and multiple dose exposure of sulfadoxine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 100% of the studies were within 2-fold and 75% were within 1.5-fold. 

  Limitations

• In the absence of adequate data on the metabolism and excretion of sulfadoxine, it was assumed that 90% was cleared renally and 10% was metabolized by the liver.

  Updates in V19

• Updated in vitro­ data
  • LogP: 4.22 -> 0.54

  Absorption Model

First-Order

  Volume of Distribution

Minimal PBPK (Method 1)

  Route of Elimination

CYP3A4 (fm = 0.50); renal clearance (fe = 0.1)

  Perpetrator DDI

• CYP2D6 Inhibitor

  Validation

• Three clinical studies describing Quinine PK were identified for model verification.
• Three clinical DDI studies where quinine was the victim of CYP-mediated DDIs were used to verify the PBPK model.  All studies were well recovered with simulated Cmax and AUC GMRs within 1.5-fold of the observed

  Limitations

• The Simcyp quinine PBPK model was able to recover interactions CYP3A inducers and inhibitors with reasonable accuracy.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time.

  Updates in V19

• Updated in vitro­ data
  • fup: 0.199 -> 0.37
  • Caco-2 A -> B Permeability: 70 x 10-6 cm/s -> 39 x 10-6 cm/s
  • Propranolol reference Permeability: 101 x 10-6 cm/s -> 45 x 10-6 cm/s
• Minimal PBPK with Vss predicted through Method 1
  • Updated retrograde clearance