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how to interpret the IVIVE for the midazolam model?? #574

Closed AyaSaleh90 closed 3 years ago

AyaSaleh90 commented 4 years ago

Hello, Now I'm replicating the midazolam PBPK model using IV bolus data from healthy individuals, and I have couple of questions regarding the model:

Regarding the IVIVE interpretation of the values implemented in the PK-Sim, like the metabolism by CYP3A4:

  1. In vitro Vmax = 850 pmol/min/mg microsomal protein
  2. Content of CYP protein in liver microsomes = 108 pmol/mg microsomal protein --> E
  3. Km = 4 umol/L --> obtained from In vitro literature
  4. Kcat= 8.761 1/min --> obtained by parameter identification using PK clinical data

1st Step:

  1. Vmax = Kcat*E = 946.2 pmol/min/mg microsomal protein

  2. CLint = Vmax/Km = 946.2 *10 ^-6 (umol/min/mg) / 4 umol/L = 0.000237 L/min/mg microsomal protein

  3. CLint = CLint MPPGL average Liver weight = 0.000237 40 1500 = 14.2 L/min

where: MPPGL is the amount of microsomal protein per gram of liver = 40 mg microsomal protein/gm liver --> implemented in PK-Sim Assumed average Liver weight= 1500 gm

2nd step, if I assumed a well-stirred model for liver (assumed): fraction unbound in plasma= 0.031 Assuming hepatic blood flow rate = 1.4 L/min

  1. Hepatic clearance = Q fu CLint / Q + (fu CLint) = 1.4 0.031 14.2 / 1.4 + (0.031 14.2) = 0.335 * 60 = 20.12 L/hr

So this value is hepatic clearance of midazolam due to the metabolism by CYP3A4, right or I'm missing something??

Thanks in advance, Aya

JanSchlender commented 4 years ago

Hi Ayatallah,

Apologies for the late reply. You may have a look at previous entries on this workflow: Duplicate of #101 Duplicate of #177