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 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

  Absorption Model

First-Order

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

CYP2C8 = 72%; Additional HLM = 28%

  Perpetrator DDI

• CYP2D6 

  Validation

• Four clinical studies describing single and multiple dose exposure of amodiaquine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 75% of the studies were 2-fold and 50% were within 1.5-fold. A clinical DDI study where amodiaquine was the victim of a CYP2C8-mediated DDI was accurately recovered using the PBPK model.

  Limitations

• Clinical data has not been used to verify amodiaquine as a perpetrator of CYP2D6-mediated DDIs

  Updates in V19

• Updated in vitro­ data
  • fu: 0.033 -> 0.089
  • B:P: 1.3 -> 1.1
  • DEAQ Ki for CYP2D6 (µM) – 1.7 -> 1.6
• Converted from minimal PBPK model to full PBPK model
  • Recalculated retrograde clearance for CYP2C8 CL_int and additional HLM CL_int

  Absorption Model

• N/A

  Volume of Distribution

• Minimal PBPK (Method 2)

  Route of Elimination

• CL_PO (non-specific) and renal clearance

  Perpetrator DDI

• CYP2D6

  Validation

• Simulations based on 1 clinical study describing multiple dose exposure of DHEA and 1 DDI study where formation of DHEA was the victim of a CYP2C9 mediated DDI were both within 1.5-fold of the observed values.

  Limitations

• Clinical data has not been used to verify DEAQ as a perpetrator of CYP2D6-mediated DDIs

  Updates in V19

• Updated DEAQ Ki for CYP2D6

  Absorption Model

First-Order

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

CYP3A4 (fm =100); renal clearance (fe = 0.05)

  Perpetrator DDI

• CYP2C9 Inhibitor
• CYP2D6 Inhibitor
• CYP3A4 Inhibitor

  Validation

• Six clinical studies describing single and multiple dose exposure of mefloquine were used the verify the PBPK model.  Most of the studies (83%) were within 1.5-fold, with all simulations falling within 2-fold of the observed values. 
• Two clinical DDI studies where mefloquine was the victim of a CYP3A4-mediated DDI were accurately recovered using the PBPK model.

  Limitations

• Only profiles of plasma concentrations assessed, many studies report blood concentrations​
• Mefloquine has significant uptake into erythrocytes and haematocrit levels typically not reported​
• Could be important in disease population (Possible time-varying B/P for Malaria patients?)​
• Cmax for doses > 750 mg over predicted ​
• fa possibly decreases with dose, more data needed to fully determine the cause​
• Most literature data extracted from graphs of mean data, difficulty determining accurate early time points due to poor image quality​
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time

  Updates in V19

• Updated in vitro­ data

• • fu_p: 0.016 -> 0.015

• • B:P ratio 1.7 -> 1.1 and subsequent re-calculation of CLint using the retrograde approach
• Converted model to full PBPK distribution model with Vss predicted through Method 2
• Sensitivity analysis of ka