Search the PBPK Model Repository

 Publication

De Sousa Mendes, M., Hirt, D., Urien, S., Valade, E., Bouazza, N., Foissac, F., Blanche, S., Treluyer, J. M., & Benaboud, S. (2015). Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. British journal of clinical pharmacology, 80(5), 1031–1041.

 Simcyp Version

V13

 Published Model Application

Prediction of exposure in pregnancy

 Absorption Model

First Order

Full PBPK

 Route of Elimination

• Renal Elimination
• Includes uptake by OCT2 and efflux by MRP4 in the kidney

 Perpetrator DDI

• None 

 Advantages and Limitations

• Model developed in healthy volunteers and verified in pregnant women.
• Renal transporters not verified with clinical data

 Model Compound Files

• v13_res_emtricitabine_simcyp_mendex2015

 Publication

De Sousa Mendes M, Chetty M. Are Standard Doses of Renally-Excreted  Antiretrovirals in Older Patients Appropriate: A PBPK Study Comparing Exposures in the Elderly Population With Those in Renal Impairment. Drugs R D. 2019 Dec;19(4):339-350.

 Simcyp Version

 V17

 Published Model Application

 Prediction of exposure in renal impairment

 Absorption Model

First Order

Full PBPK

 Route of Elimination

• Renal Elimination
• Additional non-specific clearance

 Perpetrator DDI

• None 

 Advantages and Limitations

• Model developed to extrapolate elderly populations and renally impaired populations.
• Model was verified in the elderly and young population

 Model Compound Files

• v17_res_emtricitabine_simcyp_mendex2019.cmpz

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 2)

Note: Kp scalar used

  Route of Elimination

• UGT1A9 (50%); UGT2B7(50%)

  Perpetrator DDI

• CYP1A2 Inhibitor

  Validation

• Four clinical studies describing single dose exposure of DHA were used to verify the PBPK model.  100% of studies were within 2-fold, of which 75% were within 1.5-fold.  Thus, the model performance was deemed acceptable.

  Limitations

• The model does not account for the differences in plasma fraction unbound observed in patients compared to healthy volunteers.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time.

  Updates in V19

• Updated in vitro data
  • Propranolol Papp: 30 cm/s x 106
• Converted model to full PBPK with Vss predicted through Method 2
• Updated retrograde clearance

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 2)

Note: A Kp scalar (0.04) was used in the model

  Route of Elimination

• No metabolism; a biliary CLint was input based on clinical data

  Perpetrator DDI

• None

  Validation

• Two clinical studies describing single and multiple dose exposure of atovaquone were used to verify the PBPK model. 100% of studies were within 1.5-fold.

  Limitations

• There are some data to suggest atovaquone is an inhibitor of BCRP.  This is currently not included within the model.

  Updates in V19

• Updated in vitro­ data
  • LogP: 5.8 -> 8.4
  • Caco-2 P_app > 300 x 10-6 cm/s
  • Propranolol Papp 101 x 10-6 cm/s
• Optimized ka and t_lag
• Converted from minimal PBPK model to full PBPK model