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  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 2)

Note: A Kp scalar (0.04) was used in the model

  Route of Elimination

• No metabolism; a biliary CLint was input based on clinical data

  Perpetrator DDI

• None

  Validation

• Two clinical studies describing single and multiple dose exposure of atovaquone were used to verify the PBPK model. 100% of studies were within 1.5-fold.

  Limitations

• There are some data to suggest atovaquone is an inhibitor of BCRP.  This is currently not included within the model.

  Updates in V19

• Updated in vitro­ data
  • LogP: 5.8 -> 8.4
  • Caco-2 P_app 164 > 300 x 10-6 cm/s
  • Propranolol Papp 101 x 10-6 cm/s
• Optimized ka and t_lag
• Converted from minimal PBPK model to full PBPK model

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 2)

Note: Kp scalar used

  Route of Elimination

• UGT1A9 (50%); UGT2B7(50%)

  Perpetrator DDI

• CYP1A2 Inhibitor

  Validation

• Four clinical studies describing single dose exposure of DHA were used to verify the PBPK model.  100% of studies were within 2-fold, of which 75% were within 1.5-fold.  Thus, the model performance was deemed acceptable.

  Limitations

• The model does not account for the differences in plasma fraction unbound observed in patients compared to healthy volunteers.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time.

  Updates in V19

• Updated in vitro data
  • Propranolol Papp: 30 cm/s x 106
• Converted model to full PBPK with Vss predicted through Method 2
• Updated retrograde clearance

 Absorption Model

First order

Full PBPK (Method 2)

 Route of Elimination

• CYP2B6 = 35%; CYP2D6 = 12%; CYP3A4 = 45%; Additional HLM = 5%; Renal Clearance 3% at steady state

 Perpetrator DDI

• CYP2B6 Induction
• CYP3A4 Induction

 Validation

The refined model was able to recover clinically observed concentration-time profiles of nevirapine following single and multiple dosing.

Four clinical DDI studies where nevirapine was administered with either fluconazole, rifampin, or itraconazole were used to verify the PBPK model of nevirapine as a victim. In comparison of predicted vs. observed AUC, 100% of the studies were within 1.25-fold.

Two clinical DDI studies where nevirapine was administered with either itraconazole or quinidine were used to verify the PBPK model of nevirapine as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 1.5-fold.

 Limitations

• There are no DDI studies where nevirapine was given as a single dose and so it is not possible to verify fm of CYP2B6 and CYP3A4 for a single dose.
• There is no independent DDI study to verify induction of CYP2B6.