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 Publication

Wagner et al., Physiologically-Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Co-administered with Ritonavir. J Clin Pharmacol. 2017 October ; 57(10): 1295–1304.  (FDA model)

 Simcyp Version

V13

 Absorption Model

First-Order 

Minimal PBPK

 Route of Elimination

• CYP3A4 and renal clearance

 Perpetrator DDI

• CYP3A4 time-dependent inhibitor
• CYP3A5 time-dependent inhibitor

 Advantages and Limitations

• Model developed to predict the impact of hepatic impairment on lopinavir PK.
• Accurately replicates 400 mg dose (therapeutic dose). Overprediction of 200 mg dose and underprediction of 800 mg single dose.
• DDI with ritonavir works with ritonavir file published in V18, but not the updated V19 file.
• Perpetrator DDI not verified.

 Model Compound Files

• v13_res_lopinavir_simcyp_wagner
• v13_res_ritonavir_simcyp_wagner

  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 Details

• Full PBPK (Method 2)

Note: Kp scalar and Kp adipose used

 Route of Elimination

CYP3A4 (40%); non-specific hepatic metabolism (60%)

 Perpetrator DDI

• CYP2D6 Inhibitor

 Validation

• Two clinical studies describing single dose exposure and two describing multiple dose exposure of lumefantrine were used to verify the PBPK model.
  • The single dose exposures were within 2-fold of observed for both studies.
  • The multiple dose exposures were within 1.25-fold of observed for both studies.
• Clinical DDI studies with rifampicin and efavirenz in healthy volunteers where lumefantrine was the victim of CYP3A4-mediated DDIs were over-predicted (>2-fold) using the PBPK model.
• An alternative clinical efavirenz DDI study in HIV patients and a clinical DDI with ritonavir in healthy volunteers were well predicted (within 1.25-fold of observed). As the effect of CYP3A4 inhibition was independently verified and there appeared to be variability in the extent of induction on lumefantrine PK, the fmCYP3A4 of 40% was considered verified.

 Limitations

• Plasma concentrations of lumefantrine following a single dose are less accurately predicted than those following multiple dose administration. As the Day 7 plasma concentrations following repeat administration of lumefantrine, are more critical (linked to cure rates) than after the first dose, this was deemed acceptable.
• The model can be used to prospectively predict CYP2D6-mediated DDIs but in the absence of verification of CYP2D6 inhibition, this should be accompanied by appropriate sensitivity analysis.​

 Updates in V19

• Updates in vitro data based on new information
  • B:P ratio 0.6 -> 0.55
  • CYP2D6 Ki (µM) 2.2 -> 1.8