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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

ADAM (precipitation with solution)

Full PBPK (Method 3)

 Route of Elimination

• CYP3A4 = 21%; UGT1A1 = 51%; Additional HLM = 28%

 Perpetrator DDI

• OCT2
• MATE

 Validation

Model can recover positive food effect for single and multiple dose.

The UGT1A1 fm was verified against UGT1A1 genotype study and with rifampin and atazanavir DDI studies. The fm of CYP3A4 was verified against nevirapine, rifabutin, rifampin, atazanavir, efavirenz, and carbamazepine.

One clinical study in which dolutegravir was administered with metformin was used to verify the Ki of OCT2 and MATE.

Nine clinical DDI studies where dolutegravir was administered with either nevirapine, rifampicin, rifabutin, ritonavir, atazanavir, efavirenz, and carbamazepine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 100% of the studies were 2-fold and 67% were within 1.25-fold.

 Limitations

DDI with efavirenz and carbamazepine are underpredicted, likely because efavirenz and carbamazepine are inducers of UGT1A1 which is not considered in the current efavirenz and carbamazepine compound files.