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  Absorption Model

• First-Order, fa and ka predicted by Caco-2 data

  Volume of Distribution

• Minimal (optimized to IV data)

  Route of Elimination

• fm_CYP3A4 = 80, fm_CYP2D6 = 20

  Perpetrator DDI

• Inhibition of CYP2D6

  Validation

• Model performance was verified in healthy volunteers and psychiatric patients. Two clinical studies with IV administration (7 to 10 mg) and ten clinical studies with oral administration (25 to 200 mg) were used for model verification. Simulations for eight of eleven clinical studies with a reported AUC were within 2-fold of the observed value.
• The fm_CYP1A2 was verified through simulations of chlorpromazine in smokers and non-smokers. The fm_CYP2D6­ was verified through simulations of chlorpromazine coadministered with and without quinidine.

  Limitations

• Model was developed using 10 mg IV and 100 mg PO. Use of 7-10 mg IV dosing and oral doses of 100-200 mg were verified, but predictions of oral doses <100 mg PO are overestimated.
• Model does not include P-gp efflux.
• Model is not verified for use in perpetrator DDI simulations with CYP2D6 substrates.

  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

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

 Absorption Model

First-Order 

Minimal PBPK

 Route of Elimination

• CYP3A4 and renal clearance

 Perpetrator DDI

• CYP3A4 time-dependent inhibitor
• CYP3A5 time-dependent inhibitor

 Advantages and Limitations

• Model developed to predict the impact of hepatic impairment on lopinavir PK.
• Accurately replicates 400 mg dose (therapeutic dose). Overprediction of 200 mg dose and underprediction of 800 mg single dose.
• DDI with ritonavir works with ritonavir file published in V18, but not the updated V19 file.
• Perpetrator DDI not verified.

 Model Compound Files

• v13_res_lopinavir_simcyp_wagner
• v13_res_ritonavir_simcyp_wagner