Search the PBPK Model Repository

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 19, 339–350 (2019).

 Simcyp Version

V17

 Absorption Model

• First-Order

• Full

 Route of Elimination

• Renal Clearance
• Additional non-specific clearance

 Perpetrator DDI

• None

 Advantages and Limitations

• Developed in healthy volunteers to extrapolate to elderly and renally impaired populations

 Model Compound Files

• v17_res_tenofovir_simcyp_desousamendez_2019_SD.wksz
• v17_res_tenofovir_simcyp_desousamendez_2019_young_pop.wksz
• v17_res_tenofovir_simcyp_desousamendez_2019_elderly_pop.wksz

Publication 

Liu S N, Desta Z, Gufford B T. Probenecid‐Boosted Tenofovir: A Physiologically‐Based Pharmacokinetic Model‐Informed Strategy for On‐Demand HIV Preexposure Prophylaxis[J]. CPT: pharmacometrics& systems pharmacology, 2020, 9(1): 40- 47.

 Simcyp Version

V15

 Absorption Model

• First-Order

• Full

 Route of Elimination

• Permeability-limited kidney model
• Renal uptake into the kidney by OAT1 and OAT3
• Renal efflux by MRP4
• Hepatic elimination with sinusoidal uptake

 Perpetrator DDI

• None

 Advantages and Limitations

• Based on De Sousa Mendes (2015) paper, OAT3 kinetics added to model.
• Model used to simulate tenofovir as a victim of probenecid DDI.

 Model Compound Files

• v15_res_tenofovir_simcyp_Liu_2020.wksz
• v15_res_tenofovir_simcyp_Liu_2020.cmpz

Publication 

De Sousa Mendes M, Hirt D, Urien S, Valade E, Bouazza N, Foissac F, Blanche S, Treluyer JM, Benaboud S. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. Br J Clin Pharmacol. 2015 Nov;80(5):1031-41.

 Simcyp Version

V13

 Published Model Application

Prediction of exposure in pregnancy

 Absorption Model

• First-Order

• Full

 Route of Elimination

• Renal clearance with uptake by OAT1 and efflux by MRP4
• Hepatic transporter clearance
• Additional non-specific clearance

 Perpetrator DDI

• None

 Advantages and Limitations

• Model developed to simulate PK in pregnant women after development in healthy populations.
• Low risk of DDI.
• Tenofovir is administered as a rapidly hydrolyzed prodrug (Tenofovir disoproxil fumarate). The 300 mg TDF dose was implemented as a 136 mg of tenofovir. The PK of the prodrug is not considered.
• Incorporates high degree of variability (%CV 60%) in the fraction absorbed.

 Model Compound Files

• v13_res_tenofovir_simcyp_desousamendez_2015_1mg_kg.wksz
• v13_res_tenofovir_simcyp_desousamendez_2015_3mg_kg.wksz
• v13_res_tenofovir_simcyp_desousamendez_2015_PO.wksz
• v13_res_tenofovir_simcyp_desousamendez_2015.cmpz

 Absorption Model

• ADAM, solid IR dosage form, permeability predicted by Caco-2 data, basolateral permeability scalar incorporated

Full model (method 3)

 Route of Elimination

• fm_CYP3A4 = 43.6, fm_CYP1A2 = 41.4, fm_CYP2C19 = 15.0

 Perpetrator DDI

• Not included

 Validation

• Model performance was verified in healthy adult volunteers and pediatric schistosomiasis patients. Eight clinical studies in adults (20 to 50 mg/kg PO) and one clinical study in children (20 to 60 mg/kg PO) were used for model verification. Across the adult healthy volunteer studies, eighteen of twenty-five simulated C_max values and twenty-one of twenty-five simulated AUC values were within 2-fold of the observed data. For the pediatric study in schistosomiasis patients, eleven of twelve simulated C_max and AUC values were within 2-fold of the observed data.
• The fm_CYP3A4 was verified through simulations of prazaquantel in the presence versus the absence of ketoconazole and rifampicin.

 Limitations

• Model was developed using 20 mg/kg and 40 mg/kg PO adult data. Use of 20 to 50 mg/kg PO (healthy adult volunteers) and 20 to 60 mg/kg PO (pediatric schistosomiasis patients) were verified. Utility of the model outside these dose ranges is not confirmed.
• Model assumes all CYP3A-dependent clearance is mediated by CYP3A4 (i.e., CYP3A5 is not included in the model)
• Model is not verified for use as victim of CYP1A2 and CYP2C19 interactions

  Absorption Model

First-Order

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

CYP2C8 = 72%; Additional HLM = 28%

  Perpetrator DDI

• CYP2D6 

  Validation

• Four clinical studies describing single and multiple dose exposure of amodiaquine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 75% of the studies were 2-fold and 50% were within 1.5-fold. A clinical DDI study where amodiaquine was the victim of a CYP2C8-mediated DDI was accurately recovered using the PBPK model.

  Limitations

• Clinical data has not been used to verify amodiaquine as a perpetrator of CYP2D6-mediated DDIs

  Updates in V19

• Updated in vitro­ data
  • fu: 0.033 -> 0.089
  • B:P: 1.3 -> 1.1
  • DEAQ Ki for CYP2D6 (µM) – 1.7 -> 1.6
• Converted from minimal PBPK model to full PBPK model
  • Recalculated retrograde clearance for CYP2C8 CL_int and additional HLM CL_int