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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

N/A

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

• Formed from primaquine by MAO. This is entered as ‘user-UGT’ as a surrogate within the simulator
• Pathway of elimination is not defined; elimination is assigned as IV clearance that was manually optimized to fit the clinical data

  Perpetrator DDI

• None

  Validation

• Six clinical studies describing single and multiple dose exposure of carboxyprimaquine were used to verify the PBPK model.  The AUC for all verification studies were within 1.5-fold of the observed values.

  Limitations

• Clinical data for carboxyprimaquine is highly variable

  Updates in V19

• Converted from minimal PBPK model to full PBPK model

  Absorption Model

First-Order

  Volume of Distribution

• Full PBPK (Method 2)

Note: A Kp scalar (0.5) was used in the model along with optimized partitioning into adipose tissue (Kp,adipose = 0.5) to recover the clinical observed data. 

  Route of Elimination

• CYP2B6 and CYP3A4 (non-linear kinetics); incorporates autoinduction of CYP2B6

  Perpetrator DDI

• Induction of CYP2B6

  Validation

• Two clinical studies describing single dose exposure and two describing multiple dose exposure of artemether were used to verify the PBPK model.  The single dose exposures were within 1.5-fold of observed for both studies. The multiple dose exposures were slightly over-predicted at 2.02 and 2.63-fold for the two studies.  Clinical DDI studies with ketoconazole, rifampicin and efavirenz where artemether was the victim of CYP3A4 (and CYP2B6 for efavirenz)-mediated DDIs were accurately recovered (within 1.25-fold) using the PBPK model.  A clinical DDI study with efavirenz, where artemether was the perpetrator of a CYP2B6-mediated DDI was accurately recovered (within 1.25-fold) using the PBPK model. 

  Limitations

• The tendency towards over-prediction of artemether exposure upon multiple dosing could indicate a greater extent of induction is required. However, any increase in induction potency resulted in under-prediction of single dose exposure, which is of greater importance for the therapeutic effect of artemether.

  Updates in V19

• Updated in vitro­ data
  • fu: 0.083 -> 0.038
  • B:P: 1.7 -> 1.1
• Optimized ka and t_lag
• Converted from minimal PBPK model to full PBPK model
  • Optimized CYP2B6 IndC₅₀

 Absorption Model

First order

Full PBPK (Method 3)

 Route of Elimination

• CYP3A4 = 63.2%; Additional HLM = 36.8%

 Perpetrator DDI

• CYP3A4 Inhibition
• CYP3A4 Induction

 Validation

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

Seven clinical DDI studies where rilpivirine was administered with either efavirenz, ketoconazole, rifampin, or rifabutin were used to verify the PBPK model of rilpivirine as a victim. In comparison of predicted vs. observed AUC, 85.7% of the studies were within 1.5-fold.

Three clinical DDI studies where rilpivirine was administered with either sildenafil, ethinylestradiol, or midazolam were used to verify the PBPK model of rilpivirine as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 1.25-fold.

 Limitations

The net in vivo effect of rilpivirine as either an inhibitor or an inducer of CYP3A appears to be negligible based on the available DDI studies