Search the PBPK Model Repository

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 3)
• Note: Kp scalar used

  Route of Elimination

• Undefined liver intrinsic clearance

  Perpetrator DDI

• CYP2C9 Inhibitor
• CYP3A4 Inhibitor

  Validation

• Four clinical studies describing single and multiple dose exposure of tafenoquine were used to verify the PBPK model, although some of these provided PK profiles and no PK parameters and vice versa.  Of the clinical studies describing PK parameters, the model recovered 100% of the observed PK parameters within 1.5-fold (66% within 0.8-1.25-fold) and hence the model is considered predictive.  

  Limitations

• Tafenoquine is administered with food to increase its exposure and minimize gastrointestinal side effects. The PBPK model was therefore developed to recover the PK of tafenoquine in the fed state.
• It should be noted that in the absence of information defining the fm of drug metabolizing enzymes, an undefined liver intrinsic clearance is used in the model and hence the model is not able to simulate the liability of tafenoquine as a victim of DDIs.

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 3)
• Note: Kp scalar used

  Route of Elimination

• CYP1A2, CYP2B6, CYP2C8, CYP2D6 and CYP3A4

  Perpetrator DDI

• CYP2D6 Inhibitor
• P-gp Inhibitor

  Validation

• Two clinical studies describing pyronaridine exposure were available for model verification.  100% of predicted Cmax were within 1.5-fold of those observed whereas 40% of AUC were predicted within 1.5-fold of observed. This can be explained as observed exposure at 9mg/kg dose was lower than at 6 mg/kg.  The model recovered the observed data at the 6 mg/kg dose but then over predicted that at the higher dose.

  Limitations

• One challenge in the verification of the model is the diverse ethnicities of subjects in reported clinical data and how best to reflect this in simulations.  In the absence of virtual Korean populations within the Simulator, the Caucasian population was modified in terms of bodyweight.  In the absence of supporting information, no changes to enzyme abundance (pmol/mg) were made to the population, although changes to liver weight (as a function of body weight) and hence total CYP abundance were propagated into the model.

  Updates in V19

• Switched to Method 3 to facilitate like for like comparisons for covid- 19     repurposing strategies