Search the PBPK Model Repository

 Absorption Model

ADAM (precipitation with solution)

Full PBPK (Method 3)

 Route of Elimination

• CYP3A4 = 21%; UGT1A1 = 51%; Additional HLM = 28%

 Perpetrator DDI

• OCT2
• MATE

 Validation

Model can recover positive food effect for single and multiple dose.

The UGT1A1 fm was verified against UGT1A1 genotype study and with rifampin and atazanavir DDI studies. The fm of CYP3A4 was verified against nevirapine, rifabutin, rifampin, atazanavir, efavirenz, and carbamazepine.

One clinical study in which dolutegravir was administered with metformin was used to verify the Ki of OCT2 and MATE.

Nine clinical DDI studies where dolutegravir was administered with either nevirapine, rifampicin, rifabutin, ritonavir, atazanavir, efavirenz, and carbamazepine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 100% of the studies were 2-fold and 67% were within 1.25-fold.

 Limitations

DDI with efavirenz and carbamazepine are underpredicted, likely because efavirenz and carbamazepine are inducers of UGT1A1 which is not considered in the current efavirenz and carbamazepine compound files.

Publication – MODEL 1

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

 Published Model Application

Prediction of exposure in hepatic impairment

 Absorption Model

• First-Order

• Minimal

 Route of Elimination

• CYP3A4, Non-specific metabolism, renal clearance
• Bottom-up approach for clearance, f_m,CYP3A4 was optimized with clinical DDI data with ketoconazole

 Perpetrator DDI

• CYP2B6 Competitive Inhibitor
• CYP2C9 Competitive Inhibitor
• CYP2C19 Competitive Inhibitor
• CYP2D6 Competitive Inhibitor
• CYP3A4 Competitive Inhibitor
• CYP3A5 Competitive Inhibitor

 Advantages and Limitations

• Model developed to predict the impact of CYP3A4.
• f_m,CYP3A4 was optimized with clinical DDI data with ketoconazole.
• Model recovers PK data after IV administration and single and multiple oral doses to healthy volunteers.
• Model was used to evaluate the impact of hepatic impairment.
• Perpetrator DDI not verified with clinical data.

 Model Compound Files

• v18_darunavir_wagner. cmpz
• v18_darunavir_600_mg_wagner. wksz

Publication – MODEL 2

Colbers, A., Greupink, R., Litjens, C., Burger, D., & Russel, F. G. (2016). Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy. Clinical pharmacokinetics, 55(3), 381–396. 

 Simcyp Version

V13

 Published Model Application

Prediction of exposure in pregnancy

 Absorption Model

• ADAM (transporter efflux and influx included)

• Full (permeability liver model, transporter efflux and influx included)

 Route of Elimination

• CYP3A4 and renal clearance
• ‘Bottom-up’ approach for CYP3A4 clearance from HLM data
• Non-linear CYP3A4 kinetics

 Perpetrator DDI

• None

 Advantages and Limitations

• Model developed to extrapolate darunavir pharmacokinetics in pregnancy.
• CYP3A4 enzyme kinetics derived from HLM data only.
• Linked with ritonavir PBPK model.
• Model recovers single dose PK data with and without ritonavir

 Model Compound Files

• v18_darunavir_colbers. cmpz
• v18_darunavir_600_mg_colbers. wksz
• v18_darunavir_with_ritonavir_colbers. wksz

  Absorption Model

First-Order

  Volume of Distribution

Minimal PBPK (Method 1)

  Route of Elimination

CYP3A4 (fm = 0.50); renal clearance (fe = 0.1)

  Perpetrator DDI

• CYP2D6 Inhibitor

  Validation

• Three clinical studies describing Quinine PK were identified for model verification.
• Three clinical DDI studies where quinine was the victim of CYP-mediated DDIs were used to verify the PBPK model.  All studies were well recovered with simulated Cmax and AUC GMRs within 1.5-fold of the observed

  Limitations

• The Simcyp quinine PBPK model was able to recover interactions CYP3A inducers and inhibitors with reasonable accuracy.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time.

  Updates in V19

• Updated in vitro­ data
  • fup: 0.199 -> 0.37
  • Caco-2 A -> B Permeability: 70 x 10-6 cm/s -> 39 x 10-6 cm/s
  • Propranolol reference Permeability: 101 x 10-6 cm/s -> 45 x 10-6 cm/s
• Minimal PBPK with Vss predicted through Method 1
  • Updated retrograde clearance

 Absorption Model

First order

Full PBPK (Method 3)

 Route of Elimination

• CYP3A4 = 63.2%; Additional HLM = 36.8%

 Perpetrator DDI

• CYP3A4 Inhibition
• CYP3A4 Induction

 Validation

The refined model was able to recover clinically observed concentration-time profiles of rilpivirine following single and multiple dosing.

Seven clinical DDI studies where rilpivirine was administered with either efavirenz, ketoconazole, rifampin, or rifabutin were used to verify the PBPK model of rilpivirine as a victim. In comparison of predicted vs. observed AUC, 85.7% of the studies were within 1.5-fold.

Three clinical DDI studies where rilpivirine was administered with either sildenafil, ethinylestradiol, or midazolam were used to verify the PBPK model of rilpivirine as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 1.25-fold.

 Limitations

The net in vivo effect of rilpivirine as either an inhibitor or an inducer of CYP3A appears to be negligible based on the available DDI studies