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 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

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