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 Publication

Kimoto, E., Vourvahis, M., Scialis, R. J., Eng, H., Rodrigues, A. D., & Varma, M. V. S. (2019). Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1. Drug metabolism and disposition: the biological fate of chemicals, 47(5), 493–503.

 Simcyp Version

V15

 Published Model Application

DDI prediction

 Absorption Model

ADAM; includes P-gp in the intestines

Full PBPK

 Route of Elimination

• CYP3A4
• Renal clearance
• Includes hepatic biliary clearance by OATP1B1

 Advantages and Limitations

• Model was developed to evaluate DDI of maraviroc as victim.
• Model was verified with IV and oral data.
• Model was verified as a victim of interactions with ketoconazole, ritonavir, efavirenz and rifampin

 Model Compound Files

• v15_res_maraviroc_simcyp_kimoto
• v15_res_maraviroc_simcyp_kimoto_iv_3mg
• v15_res_maraviroc_simcyp_kimoto_iv_10mg
• v15_res_maraviroc_simcyp_kimoto_iv_30mg
• v15_res_maraviroc_simcyp_kimoto_po_150mg_bid

Publication – MODEL 1

Wagner et al., Physiologically-Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Co-administered with Ritonavir. J Clin Pharmacol. 2017 October ; 57(10): 1295–1304.  (FDA model)

 Simcyp Version

V13

 Published Model Application

Prediction of exposure in hepatic impairment

 Absorption Model

• First-Order

• Minimal

 Route of Elimination

• CYP3A4, Non-specific metabolism, renal clearance
• Bottom-up approach for clearance, f_m,CYP3A4 was optimized with clinical DDI data with ketoconazole

 Perpetrator DDI

• CYP2B6 Competitive Inhibitor
• CYP2C9 Competitive Inhibitor
• CYP2C19 Competitive Inhibitor
• CYP2D6 Competitive Inhibitor
• CYP3A4 Competitive Inhibitor
• CYP3A5 Competitive Inhibitor

 Advantages and Limitations

• Model developed to predict the impact of CYP3A4.
• f_m,CYP3A4 was optimized with clinical DDI data with ketoconazole.
• Model recovers PK data after IV administration and single and multiple oral doses to healthy volunteers.
• Model was used to evaluate the impact of hepatic impairment.
• Perpetrator DDI not verified with clinical data.

 Model Compound Files

• v18_darunavir_wagner. cmpz
• v18_darunavir_600_mg_wagner. wksz

Publication – MODEL 2

Colbers, A., Greupink, R., Litjens, C., Burger, D., & Russel, F. G. (2016). Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy. Clinical pharmacokinetics, 55(3), 381–396. 

 Simcyp Version

V13

 Published Model Application

Prediction of exposure in pregnancy

 Absorption Model

• ADAM (transporter efflux and influx included)

• Full (permeability liver model, transporter efflux and influx included)

 Route of Elimination

• CYP3A4 and renal clearance
• ‘Bottom-up’ approach for CYP3A4 clearance from HLM data
• Non-linear CYP3A4 kinetics

 Perpetrator DDI

• None

 Advantages and Limitations

• Model developed to extrapolate darunavir pharmacokinetics in pregnancy.
• CYP3A4 enzyme kinetics derived from HLM data only.
• Linked with ritonavir PBPK model.
• Model recovers single dose PK data with and without ritonavir

 Model Compound Files

• v18_darunavir_colbers. cmpz
• v18_darunavir_600_mg_colbers. wksz
• v18_darunavir_with_ritonavir_colbers. wksz

  Absorption Model

• First-Order

  Volume of Distribution 

• Full PBPK (Method 2) 

Note: Kp scalar used

  Route of Elimination

• Non-specific hepatic metabolism (metabolizing enzymes not known)

  Perpetrator DDI

• OCT1 and OCT2 inhibitor

  Validation

• Three clinical studies were available for model verification.  100% of simulated Cmax and AUC were within 1.5-fold of observed and hence the model performance was deemed acceptable.

  Limitations

• The current model does not describe enzyme specific metabolism of pyrimethamine as there are no data for specific routes of metabolism.​

The current model does not mechanistically describe the absorption of pyrimethamine as the ADAM model over-predicts the extent of absorption. Although pyrimethamine is described as well absorbed in some literature, further analysis of the IV and PO data did not support this. 

  Updates in V19

• Updated in vitro­ data
  • fup: 0.085 -> 0.095