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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

• 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