Search the PBPK Model Repository

  Absorption Model

First-Order

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

Formed by CYP2C19, CYP3A4; unknown clearance mechanism

  Perpetrator DDI

• CYP2D6 Inhibitor

  Validation

• Proguanil and cycloguanil files were built using in vitro and clinical (Jeppersen et al., 1997) data
• 5 clinical studies describing single and multiple dose exposure of cycloguanil were used to verify the PBPK model. 60% of studies were within 2-fold, of which 40% were within 1.5-fold.
• A clinical DDI study where proguanil was the victim of a CYP2C19-mediated DDI was accurately recovered using the PBPK model.  

  Limitations

• Prediction of cycloguanil exposure was complicated by not knowing the polymorphism classification of subjects in each study, hence the model performance was deemed acceptable using the criteria of being within 2-fold of observed.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time

  Updates in V19

• Recalculated fm values using the corrected dose administered in Jeppesen et al., 1997
• Previous version used paper calculation of total clearance which did not account for the weight of the salt in the 200 mg dose administered
• Model converted from minimal to full PBPK distribution model
• Updated in vitro data
• Updated CYP2D6 IC₅₀

 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

 Absorption Model

ADAM (Solution)

Full PBPK (Method 2)

 Route of Elimination

• CYP3A4 = 19.5 %, CYP2C19 = 33%, additional HLM = 20%, biliary clearance =26 %, renal clearance = 1.5% at steady state

 Perpetrator DDI

• CYP3A4 competitive inhibition, Mechanism-Based Inhibition and Induction
• P-gp Inhibition

 Validation

The refined model was able to recover clinically observed concentration-time profiles of nelfinavir following single and multiple dosing.

Six clinical DDI studies where nelfinavir was administered with either ritonavir, rifampicin, rifabutin, efavirenz, and nevirapine were used to verify the PBPK model of nevirapine as a victim. In comparison of predicted vs. observed AUC, 100% of the studies were within 1.5-fold.

Nine clinical DDI studies where nevirapine was administered with either alfentanil, midazolam, simvastatin, atorvastatin, rifabutin, or digoxin were used to verify the PBPK model of nevirapine as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 2-fold and 78% were within 1.25-fold.

 Limitations

• Single oral dose exposure is underpredicted (generally within 2-fold)