Fed State Physiologies

Understanding the effects of food on pharmacokinetics is a key aspect for compounds with a pH- dependent solubility or low solubility. This understanding is particularly important for compounds that are sensitive to increased gastric pH or require the effect of bile salts to enhance solubility and dissolution. The GastroPlus® physiologies account for six key differences between the fasted and fed states.

• Increased gastric emptying time.

• Increased gastric volume.

• Increased gastric pH.

• Decreased upper intestine pH.

• Increased bile salt concentration.

• Increased hepatic blood flow rate.

The Fasted and Fed State physiologies have the following characteristics:

• For both the Human Fasted and Human Fed State physiologies, the intestinal compartments are divided into six small intestine compartments, one caecum compartment, and one colon compartment. The pHs, lengths, transit times, and radii for all these compartments are as physiologically accurate as the literature allows.

• For many drugs, no significant difference is noticed between the results obtained with the two physiologies; however, for ionizable drugs that have a significant difference in solubility between pH 5.0 and 7.5 (which occurs in the caecum and colon), major differences can be observed.

• For all Fed State physiologies, the gastric emptying time and the bile salt concentration are based on the calories and fat content of the meal consumed. See:

• Gastric transit time

• Fed Meal % fat effect on bile concentration

Gastric transit time

The effect of meal calories and type on gastric emptying rate has been studied extensively in literature ^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15} . We compiled data from a number of relevant publications, and then developed a correlation between the calories in the meal and gastric emptying time as shown in Figure 1-2.

Figure 1-2:  Correlation between the calories in a meal and gastric emptying time

To allow the correlation to be scaled to subjects of much lower weight, including pediatrics, the x-axis was defined as % of daily calories in the meal for the gastric emptying function. The conversion of the meal calories into % daily calories requires information from the literature about the daily caloric intake habits of subjects versus age and gender ^{16 17} as well as from the National Health and Nutrition Examination Survey (NHANES, http://www.cdc.gov/nchs/nhanes.htm). A piece-wise polynomial was developed to fit the male and female calories versus age and gender and used with the calorie input to define % daily calories as shown in Figure 1-3.

Figure 1-3:  Daily input calories versus age for male and female

Another factor that impacts the gastric emptying time is the shape of the emptying profile. Most of the literature for fed state emptying rates indicates that the profile more closely resembles a zero-order emptying instead of the first-order exponential profile, which is indicative of the fasted state. Table 1-1 summarizes this information.

Table 1-1:  Qualitative evaluation of gastric emptying profile shape

In addition to the actual emptying profiles themselves, we previously looked at a subset of PK data that explored the effect of % fat and calories. While it is beyond the scope of this guide to look at in-depth model development for all compounds, Table 1-2 summarizes overall prediction trends with eight different Fed State physiologies. The results indicate that with the default gastric emptying time calculation and bile salt concentration adjustment, we are generally making better predictions in the fed state.

References are cited where appropriate in Table 1-2. All internal studies used confidential data.

Table 1-2:  Evaluation of GastroPlus® Fed State physiology settings on PK predictions for eight compounds

Fed Meal % fat effect on bile concentration

The % fat in a meal can impact multiple aspects of drug dissolution. Additional fat in a meal can cause the drug to partition into the fat micelles in a higher amount than in a low-fat meal, which is essentially an “effective” increase in solubility and therefore, in the dissolution rate. Although we do not have the ability to track the concentration of dietary fats and know their capacity for drug partitioning, we can address the increased bile production that high fat diets cause. Studies using imaging methods or direct measurement have shown higher biliary excretion ^{37 38} . An indirect measurement of total bile acid excretion comes via the measurement of bile acids in the feces that escaped re- uptake. In high fat diets, the fecal concentration of bile increased by 1.3 to 2-fold ^{39 40 41} . Bevernage also directly measured different bile concentrations after ingestion of two nutritional drinks of moderate or high fat content ⁴² . Based on the bile excretion and fecal concentration data, we built a bile secretion, transit, and uptake physiology to predict steady state bile concentrations that would result in 1.3- to 2-fold increases in bile concentration in feces. This averaged with the direct measurement of Bevernage served as a basis for the correlation we developed between % fat in a meal and bile concentration in the intestinal lumen. As shown in Equation 1-4 and Table 1-3, this correlation is a second order polynomial where the concentration of bile C_bile,N in any compartment N can be calculated from the constants A_(2,N), A_(1,N), and A_(0,N).

Equation 1-4:  Second-order polynomial for the prediction of bile salt concentration in the intestinal lumen based on % fat in a meal

Table 1-3:   Polynomial coefficients for Equation 1-4