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  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

  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 (dose and food-dependent fa – saved in different models)

  Volume of Distribution

• Full PBPK (Method 2)
• Notes: Includes a Kp scalar and Kpadipose

  Route of Elimination

• CYP3A4 (80%), CYP2C9 (10%), CYP2C19 (10%)

  Perpetrator DDI

• CYP3A4 Inhibitor

  Validation

• Two clinical studies with fasted and fed groups at varying dose levels describing single and multiple dose exposure of piperaquine were used to verify the PBPK model. All of the simulated studies were within 1.5-fold of the observed values. 
• A clinical DDI study where piperaquine was the victim of a CYP3A4-mediated DDI was accurately recovered using the PBPK model as well as a CYP3A4 perpetrator DDI with the sensitive substrate midazolam.

  Limitations

• Requires separate files for low and high dose due to dose-dependant fa​
• Cmax overprediction, likely due to formulation differences​
• Additional verification for DDIs would be ideal although studies are currently not available in literature

  Updates in V19

• Updated in vitro­ data
• LogP
• Converted model to full PBPK with Vss predicted through Method 2