PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol

Abstract

Background: A "physiologically based pharmacokinetic" (PBPK) approach uses a realistic model of the animal to describe the pharmacokinetics. Previous PBPKs have been designed for specific solutes, required specification of a large number of parameters and have not been designed for general use.

Methods: This new PBPK program (PKQuest) includes a "Standardhuman" and "Standardrat" data set so that the user input is minimized. It has a simple user interface, graphical output and many new features: 1) An option that uses the measured plasma concentrations to solve for the time course of the gastrointestinal, intramuscular, intraperotineal or skin absorption and systemic availability of a drug - for a general non-linear system. 2) Capillary permeability limitation defined in terms of the permeability-surface area products. 4) Saturable plasma and tissue protein binding. 5) A lung model that includes perfusion-ventilation mismatch. 6) A general optimization routine using either a global (simulated annealing) or local (Powell) minimization applicable to all model parameters.

Results: PKQuest was applied to measurements of human propranolol pharmacokinetics and intestinal absorption. A meal has two effects: 1) increases portal blood flow by 50%; and 2) decreases liver metabolism by 20%. There is a significant delay in the oval propranolol absorption in fasting subjects that is absent in fed subjects. The oral absorption of the long acting form of propranolol continues for a period of more than 24 hours.

Conclusions: PKQuest provides a new general purpose, easy to use, freely distributed www.pkquest.com and physiologically rigorous PBPK software routine.

Figure 1

Flow diagram used for PBPK model. Each box represents a well-stirred compartment and each arrow is an input or output to the organ.

Figure 2

Comparison of PKQuest model prediction and experimental plasma propranolol concentration data (squares) of fagen et. al. [24].

Figure 3

Comparison of PKQuest model prediction and experimental data for fasted subjects. Figure 3A shows the predicted venous plasma concentration for IV propranolol, and fig. 3B shows the predicted time course of absorption (squares) and peripheral availability (diamonds) for oral propranolol using experimental data of Olanoff et. al [5].

Figure 4

Same as figure 3 for case where propranolol is given either IV or orally at the same time as a standard meal.

Figure 5

Time course of absorption (squares) and peripheral availability (diamonds) for oral (60 mg) standard (fig. 5A) or long acting (fig. 5B) propranolol using experimental data of Takahashi et. al [25].

Figure 6

Simulated venous plasma concentration for oral administration of standard (fig. 6A) and sustained release (fig. 6B) form of propranolol: A) Standard form: 40 mg, three times per day; B) Sustained release form: 120 mg, once per day.

Figure 7

Diagram showing the parameters involved in the exchange of solute between the capillary and the extravascular (tissue) space. The variable C is the total concentration, c is the free water concentration and F is the blood flow. The subscript A indicates arterial, T tissue and V venous compartments.

Figure 8

Model venous concentration for the case of an oral input described by eq. 29. The squares indicate the discrete time points where the venous concentration is sampled. These discrete time points are used as input for the results shown in fig. 9.

Figure 9

Predicted time course of absorption using the discrete sampled time points (fig. 8). The predicted time course should equal the function (eq. 29) that was used to generate these time points.