Search the PBPK Model Repository

  Absorption Model

First-Order

  Volume of Distribution

• Full PBPK (Method 2)

Note: A Kp scalar (0.5) was used in the model along with optimized partitioning into adipose tissue (Kp,adipose = 0.5) to recover the clinical observed data. 

  Route of Elimination

• CYP2B6 and CYP3A4 (non-linear kinetics); incorporates autoinduction of CYP2B6

  Perpetrator DDI

• Induction of CYP2B6

  Validation

• Two clinical studies describing single dose exposure and two describing multiple dose exposure of artemether were used to verify the PBPK model.  The single dose exposures were within 1.5-fold of observed for both studies. The multiple dose exposures were slightly over-predicted at 2.02 and 2.63-fold for the two studies.  Clinical DDI studies with ketoconazole, rifampicin and efavirenz where artemether was the victim of CYP3A4 (and CYP2B6 for efavirenz)-mediated DDIs were accurately recovered (within 1.25-fold) using the PBPK model.  A clinical DDI study with efavirenz, where artemether was the perpetrator of a CYP2B6-mediated DDI was accurately recovered (within 1.25-fold) using the PBPK model. 

  Limitations

• The tendency towards over-prediction of artemether exposure upon multiple dosing could indicate a greater extent of induction is required. However, any increase in induction potency resulted in under-prediction of single dose exposure, which is of greater importance for the therapeutic effect of artemether.

  Updates in V19

• Updated in vitro­ data
  • fu: 0.083 -> 0.038
  • B:P: 1.7 -> 1.1
• Optimized ka and t_lag
• Converted from minimal PBPK model to full PBPK model
  • Optimized CYP2B6 IndC₅₀

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

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

 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.

 Model Compound Files

• v13_res_lamivudine_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 population

 Model Compound Files

• v17_res_ lamivudine_simcyp_mendex2019

 Publication

Shah, K., Fischetti, B., Cha, A., & Taft, D. R. (2020). Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine. Current drug discovery technologies, 17(3), 387–396.

 Simcyp Version

V18

 Published Model Application

Prediction of exposure in renal impairment

 Absorption Model

First Order

Full (mechanistic kidney model)

 Route of Elimination

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

 Perpetrator DDI

• None 

 Advantages and Limitations

• Model developed to renally impaired populations.

 Model Compound Files

• v18_res_ lamivudine_simcyp_shah2020