Search the PBPK Model Repository

Absorption Model

• First-Order

Volume of Distribution 

• Full PBPK (Method 2)

Routes of Elimination

• 89% MAO (entered using ‘user-UGT’ as a surrogate in the Simulator), 11% CYP2D6

Perpetrator DDI

• CYP1A2 Inhibitor (in vitro)

Validation

•  6 studies with single (15 to 45 mg) and multiple (15 mg QD) dosing. 100% of Cmax and AUC values within 1.5-fold.
• No clinical DDI studies to verify contribution of metabolic routes

Limitations

•  The active metabolites of primaquine have not characterized due to their instability. Therefore, a PBPK model for active metabolites cannot be developed in their own right.
• Qualitative data suggests a role of P-gp, however, Jmax and Km values have not been measured.
• There is evidence of enantiomer specific metabolism for primaquine which has not been considered in the current model.

Updates in Version 19

• Updated in vitro protein and blood binding data and subsequent back calculation of CLint (retrograde approach)
  •  f_u: 0.19 -> 0.26
  • B:P: 1 -> 0.82

• Converted from minimal PBPK model to full PBPK model

 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