Human physiologically based pharmacokinetic model for propofol

Abstract

BACKGROUND: Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol. METHODS: PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. RESULTS: The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. CONCLUSION: A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed.

Figures

Figure 1

Schematic diagram of the PBPK model. The organ "portal" refers to all the organs drained by the portal vein. The connective tissue is divided between two organs: "tendon" with a relatively low blood flow and "other" with a higher blood flow.

Figure 5

Individual PBPK model fits to the experimental data for the young subjects. The values of the 3 parameters that provided the best fit for each individual subject are listed: Tclr = intrinsic liver clearance; frdose = fraction of the bolus dose sequestered in first passage through the lung; T = time constant for release of sequestered propofol. The value in parenthesis following Tclr is the fraction of the total liver blood flow that is cleared (eq. (10)).

Figure 6

Individual PBPK model fits to the experimental data for the middle aged subjects. The values of the 3 parameters that provided the best fit for each individual subject are listed (see fig. 5). For 6 of the 8 subjects there was no pulmonary sequestration of the bolus dose. In order to fit the data for subject 2–4, a small amount of extra-hepatic metabolism was required (kidney clearance = Tclrkid = 35).

Figure 7

Individual PBPK model fits to the experimental data for the old subjects. No pulmonary sequestration of the bolus dose was required in any subject in this age group. Therefore, there is only 1 adjustable parameter (intrinsic liver clearance, Tclr).

Figure 2

Error in fitting the kinetics following the bolus injection (0 to 60 minutes) using the PBPK parameters determined by fitting the constant infusion kinetics (>60 minutes) assuming no pulmonary sequestration. The solid lines are the PBPK model predictions and the squares are the experimental results of Schnider et. al. [20]. The top row shows the entire time course and the bottom shows the first 60 minutes. Absolute concentration on left and semi-log plot of concentration versus time on right.

Figure 3

Same experimental data as in figure 2 except that 60% of the bolus dose has been sequestered in the lung and released with a time constant of 80 minutes.

Figure 4

Effect of pulmonary sequestration of 0, 10, 25 or 50% of the continuously infused dose. Same experimental data as in figure 2 with 60% sequestration of the bolus dose. The sequestered propofol is released with a time constant of 80 minutes.

Figure 8

Age dependence of the fraction sequestered in lung. The dashed line is the linear regression for the data (eq. (13)).

Figure 9

PBPK model fits to the experimental data for the young subjects using the same age dependent parameters for all subjects: fractional liver clearance = 0.76; fraction sequestered described by eq. (13), and T = 80 minutes.

Figure 10

PBPK model fits to the experimental data for the middle-aged subjects using the same age dependent parameters for all subjects (see fig. 9).

Figure 11

PBPK model fits to the experimental data for the old subjects using the same age dependent parameters for all subjects (see fig. 9).

Figure 12

Comparison of NONMEM (Schnider et. al., Table 2 [20]) and PBPK model predictions for a standard male (21% body fat, age 53, weight 77 kg and height 177 cm). The top row shows the model predictions for a 1-hour constant infusion of 100 μg/kg/min followed by a 9 hour washout (left, absolute plot; right, semi-log plot). The middle row shows the model predictions when the washout period is extended to 49 hours. The bottom row compares the model predictions for a 5 day constant infusion of 100 μg/kg/min.

Figure 13

Same as fig. 12, except for an obese female with 47% body fat (age 53, weight 77 kg and height 150 cm).

Figure 14

Comparison of arterial blood concentration in normal weight (black) and morbidly obese subjects (red). The propofol was infused at a constant rate of 0.1 mg/kg/min for 180 minutes and the washout was followed for 8 hours (top panel) or 5 days (bottom panel).

Figure 15

Comparison of time for eye opening after a 180 minute constant infusion in normal weight (black) and morbidly obese subjects (red). Same conditions as fig. 14, but only the first 20 minutes of the washout is plotted. The dashed line indicates the arterial concentration associated with the first eye opening.

Figure 16

Comparison of arterial blood concentration in normal weight (black) and morbidly obese subjects (red). Ten-day constant infusion of 0.1 mg/kg/min.

Figure 17

Comparison of washout kinetics in normal weight (black) and morbidly obese subjects (red). The 10 day constant infusion rate has been adjusted so that the concentration at the end of 10 days is identical for the normal and obese subjects (normal: 0.1 mg/kg/min; obese: 0.058 mg/kg/min). Only the first 60 minutes of the washout is plotted.