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  Absorption Model

• First-Order

  Volume of Distribution 

• Full PBPK (Method 2) 

Note: Kp scalar used

  Route of Elimination

• Non-specific hepatic metabolism (metabolizing enzymes not known)

  Perpetrator DDI

• OCT1 and OCT2 inhibitor

  Validation

• Three clinical studies were available for model verification.  100% of simulated Cmax and AUC were within 1.5-fold of observed and hence the model performance was deemed acceptable.

  Limitations

• The current model does not describe enzyme specific metabolism of pyrimethamine as there are no data for specific routes of metabolism.​

The current model does not mechanistically describe the absorption of pyrimethamine as the ADAM model over-predicts the extent of absorption. Although pyrimethamine is described as well absorbed in some literature, further analysis of the IV and PO data did not support this. 

  Updates in V19

• Updated in vitro­ data
  • fup: 0.085 -> 0.095

  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