Search the PBPK Model Repository

  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