Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters


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only elimination pathway for the parent drug and a complete release of the metabolite into systemic circulation without prior elimination in the organ where it is formed is assumed.

       1.2.10.4 Limiting Conditions

      1 Metabolite disposition is formation rate‐limited (kel,M > kf,M ) – commonly observed

      2 Metabolite disposition is elimination rate‐limited (kf,M > kel,M )

      3 Neither of the two steps above are rate limiting

      In the first case, when metabolite disposition is limited by its formation, the half‐life of parent is greater than that of its metabolite and the following equation holds:

      CLM is the clearance of the metabolite, CLf,M is the metabolic clearance of the parent drug related to the formation of metabolite, VM is the volume of distribution of the metabolite, and V is the volume of distribution of the parent drug. The PK profiles of the parent drug and its metabolite are characterized by parallel terminal slopes (see Figure 1.9). The metabolite is eliminated as soon as it is formed. Consequently, the right‐hand side of Equation 1.50 becomes zero leading to

      (1.53)equation

      In the second case, the metabolite disposition is limited by its elimination and the half‐life of the metabolite is greater than that of its parent drug. This may lead to accumulation of the metabolite in the body and requires careful safety monitoring.

      Lastly, in the event of comparable half‐lives of drug and metabolite, the terminal slope of the metabolite appears to decline slower than would be expected from its elimination rate constant, sustained by the parent drug.

Schematic illustration of limiting conditions on metabolite disposition.

       1.2.10.5 Drug‐Metabolite Plasma Concentration Relationships After Single Drug Administration

      Integrating Equation 1.54,

      where AUCM and AUC are the areas under the concentration‐time profiles of metabolite and parent drug, respectively. Recognizing that CLf,M is the product of fraction metabolized (fm ) and the total clearance (CL) of the parent drug,

      (1.57)equation

       1.2.10.6 Steady‐State Metabolite Kinetics

      At steady state, the rate of change in the amount of metabolite in the body is zero, making the left‐hand sides of Equations 1.50 and 1.54 equal zero. It follows that the amount and concentration of the metabolite in the body at steady state are:

      (1.58)equation

       1.2.10.7 First‐Pass Metabolite Production


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