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 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

 Absorption Model

• ADAM, solid IR dosage form, permeability predicted by Caco-2 data, basolateral permeability scalar incorporated

Full model (method 3)

 Route of Elimination

• fm_CYP3A4 = 43.6, fm_CYP1A2 = 41.4, fm_CYP2C19 = 15.0

 Perpetrator DDI

• Not included

 Validation

• Model performance was verified in healthy adult volunteers and pediatric schistosomiasis patients. Eight clinical studies in adults (20 to 50 mg/kg PO) and one clinical study in children (20 to 60 mg/kg PO) were used for model verification. Across the adult healthy volunteer studies, eighteen of twenty-five simulated C_max values and twenty-one of twenty-five simulated AUC values were within 2-fold of the observed data. For the pediatric study in schistosomiasis patients, eleven of twelve simulated C_max and AUC values were within 2-fold of the observed data.
• The fm_CYP3A4 was verified through simulations of prazaquantel in the presence versus the absence of ketoconazole and rifampicin.

 Limitations

• Model was developed using 20 mg/kg and 40 mg/kg PO adult data. Use of 20 to 50 mg/kg PO (healthy adult volunteers) and 20 to 60 mg/kg PO (pediatric schistosomiasis patients) were verified. Utility of the model outside these dose ranges is not confirmed.
• Model assumes all CYP3A-dependent clearance is mediated by CYP3A4 (i.e., CYP3A5 is not included in the model)
• Model is not verified for use as victim of CYP1A2 and CYP2C19 interactions