Search the PBPK Model Repository

 Absorption Model

•   First-Order

 Volume of Distribution 

•   Full PBPK (Method 2)

  Note: Kp scalar used

 Route of Elimination

•   CYP2C19, CYP3A4, renal clearance

 Perpetrator DDI

•   CYP2D6 Inhibitor

 Validation

• Proguanil and cycloguanil files were built using in vitro and clinical (Jeppersen et al., 1997) data
• 3 clinical studies describing single and multiple dose exposure of proguanil were used to verify the PBPK model. 66% of studies were within 2-fold, of which 33% were within 1.5-fold. 
• A clinical DDI study where proguanil was the victim of a CYP2C19-mediated DDI was accurately recovered using the PBPK model.  

 Limitations

• Prediction of proguanil exposure was complicated by not knowing the polymorphism classification of subjects in each study, hence the model performance was deemed acceptable using the criteria of being within 2-fold of observed.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time
• With a large CL_Rcomponent and chemical relation to metformin, we hypothesise that proguanil may be a substrate for active transport in the kidney. However, owing to a lack of mechanistic information relating to active transport this cannot be built into the model.​

 Updates in V19

• Modification of fm values
• Model converted from minimal to full PBPK distribution model
• Updated CYP2D6 IC50

  Absorption Model

First-Order

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

Formed by CYP2C19, CYP3A4; unknown clearance mechanism

  Perpetrator DDI

• CYP2D6 Inhibitor

  Validation

• Proguanil and cycloguanil files were built using in vitro and clinical (Jeppersen et al., 1997) data
• 5 clinical studies describing single and multiple dose exposure of cycloguanil were used to verify the PBPK model. 60% of studies were within 2-fold, of which 40% were within 1.5-fold.
• A clinical DDI study where proguanil was the victim of a CYP2C19-mediated DDI was accurately recovered using the PBPK model.  

  Limitations

• Prediction of cycloguanil exposure was complicated by not knowing the polymorphism classification of subjects in each study, hence the model performance was deemed acceptable using the criteria of being within 2-fold of observed.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time

  Updates in V19

• Recalculated fm values using the corrected dose administered in Jeppesen et al., 1997
• Previous version used paper calculation of total clearance which did not account for the weight of the salt in the 200 mg dose administered
• Model converted from minimal to full PBPK distribution model
• Updated in vitro data
• Updated CYP2D6 IC₅₀