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  Absorption Model

• First-Order

  Volume of Distribution

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

  Route of Elimination

• CYP1A2, CYP2B6, CYP2C8, CYP2D6 and CYP3A4

  Perpetrator DDI

• CYP2D6 Inhibitor
• P-gp Inhibitor

  Validation

• Two clinical studies describing pyronaridine exposure were available for model verification.  100% of predicted Cmax were within 1.5-fold of those observed whereas 40% of AUC were predicted within 1.5-fold of observed. This can be explained as observed exposure at 9mg/kg dose was lower than at 6 mg/kg.  The model recovered the observed data at the 6 mg/kg dose but then over predicted that at the higher dose.

  Limitations

• One challenge in the verification of the model is the diverse ethnicities of subjects in reported clinical data and how best to reflect this in simulations.  In the absence of virtual Korean populations within the Simulator, the Caucasian population was modified in terms of bodyweight.  In the absence of supporting information, no changes to enzyme abundance (pmol/mg) were made to the population, although changes to liver weight (as a function of body weight) and hence total CYP abundance were propagated into the model.

  Updates in V19

• Switched to Method 3 to facilitate like for like comparisons for covid- 19     repurposing strategies

 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.