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 Absorption Model

First order (different absorption parameters for each formulation)

Minimal PBPK with Vsac and Q (Method 2)

 Route of Elimination

• CYP3A4 = 95%; Additional HLM = 5%

 Perpetrator DDI

• CYP3A4 Mechanism Based Inhibition

 Validation

The exposure of 1000mg BID saquinavir with 100 mg BID ritonavir regimen for hard gel were reasonably well recovered (3/3 within 2-fold). With the exception of the 1000 mg BID saquinavir with 100 mg BID ritonavir regimen for soft gel, the exposures of ritonavir-boosted regimens were well recovered (4/5 within 1.5-fold).

Ten clinical DDI studies where saquinavir (soft gel) was administered with either ritonavir, cimetidine, ketoconazole, rifampin, erythromycin, or rifabutin were used to verify the PBPK model of saquinavir as a victim. In comparison of predicted vs. observed AUC, 80% of the studies were within 2-fold.

Two clinical DDI studies where saquinavir (hard gel) was administered with either ritonavir or nelfinavir were used to verify the PBPK model of saquinavir (hard gel) as a victim. In comparison of predicted vs. observed AUC, 50% of the studies were within 2-fold.

Three clinical DDI studies where saquinavir was administered with either midazolam or rifabutin were used to verify the PBPK model of rifabutin (soft gel) as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 2-fold.

 Limitations

• The variability within studies has presented a significant challenge to developing a single model to recover all data.

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 3)
• Note: Kp scalar used

  Route of Elimination

• Undefined liver intrinsic clearance

  Perpetrator DDI

• CYP2C9 Inhibitor
• CYP3A4 Inhibitor

  Validation

• Four clinical studies describing single and multiple dose exposure of tafenoquine were used to verify the PBPK model, although some of these provided PK profiles and no PK parameters and vice versa.  Of the clinical studies describing PK parameters, the model recovered 100% of the observed PK parameters within 1.5-fold (66% within 0.8-1.25-fold) and hence the model is considered predictive.  

  Limitations

• Tafenoquine is administered with food to increase its exposure and minimize gastrointestinal side effects. The PBPK model was therefore developed to recover the PK of tafenoquine in the fed state.
• It should be noted that in the absence of information defining the fm of drug metabolizing enzymes, an undefined liver intrinsic clearance is used in the model and hence the model is not able to simulate the liability of tafenoquine as a victim of DDIs.