Search the PBPK Model Repository

  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.

 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