Gastric Emptying

Before the formulation is emptied from the stomach, various methods may be applied to prolong gastric residence [13]. The impact of a species' pylorus diameter and gastric contractions on an integral tablet's dimension has been discussed [14, 15]. The impact of food on gastric emptying has also been well studied. However, in comparing the effect of food on gastric emptying in different species, the meal composition needs careful consideration. Calories, volume, consistency, fat, protein, carbohydrates all play important roles in gastric emptying, as well as species-dependent physiologic response to the stimulus. Only when the meals are carefully controlled over a wide range can one determine the advantages and disadvantages of a particular animal model. Additionally, the meal may need to be different for an animal model that mimics the impact of food on gastric emptying vs. solubilizing an active pharmaceutical ingredient (API) that has poor wetting and/or aqueous solubility characteristics. Some investigators have attempted to mimic the Food and Drug Administration (FDA) high fat meal by simply blending the entire meal, and then feeding the meal to dogs [16]. This meal corresponds to 1,000 calories (kcal), 50% of which comprises fat.

In one pharmacokinetic project, the lipophilic drug ziprasidone HCl was orally administered to ten dogs in the fasted state and with several meals. Gastric pH and emptying was also recorded in matching studies with a radio-telemetric Heidelberg capsule (Heidelberg International, Electro-Medical Devices, Inc. Norcross, Ga.). The typical meal is fed once a day and consists of 300-350 g dry dog food (e.g. ProLab Canine 1600, PMI Feeds Inc., St. Louis, MO: Crude protein 21%, Crude Fat 8%, Crude Fiber 5.5%, moisture 11%) totaling 1,470 kcal. The standard high fat breakfast was scaled down for a 10 kg dog with a combination of dry dog food and olive oil. Olive oil was selected due to its precedence in food studies [17]. The high-fat meal consisted of 14 g of dry dog food and 8 g of olive oil (9.1 g fat (41%), 128 kcal). After a 40 h fast (water available) the test meal was completely eaten by the dog. Preliminary studies suggested that the usual rations of dry dog food (approximately 300 g per dog) inhibited gastric emptying of the Heidelberg capsule for >12 h. A meal consisting entirely of 50 g dry dog food was selected as a low-fat meal (4 g fat (8%), 210 kcal).

The results of these meals on gastric emptying and pH are shown in Table 4.1. The peak gastric pH was tabulated for fed dogs. Gastric pH in the fasted dog seemed

Table 4.1 Summary of gastric pH and gastric emptying time (GET) values. Meals shown are "Normal rations" (300 g dry dog chow), "Low-fat" (50 g dry dog chow) and "High-fat" (a mixture of 14 g dry dog chow and 8 g olive oil)

Parameter

Fasting

Meal

Normal rations

Low-fat

High-fat

pHa

2.3

3.5

3.6

2.6

GET (h)

1.0 ± 0.8

12-24

4.2 ± 0.9*

6.5 ± 1.7**

nb

10

2

9

4

a For the fasted condition, only the average pH is shown; the peak pH values are shown for all fed conditions (see text for details) b Number of studies

* Significantly different from fasted (ANOVA, p < 0.01) ** Significantly different from the low fat (ANOVA, p < 0.01)

a For the fasted condition, only the average pH is shown; the peak pH values are shown for all fed conditions (see text for details) b Number of studies

* Significantly different from fasted (ANOVA, p < 0.01) ** Significantly different from the low fat (ANOVA, p < 0.01)

Table 4.2 Summary pharmacokinetics after ziprasidone HCl administration to dogs under fasted and fed conditions. See Table 4.1 for meal definitions

Meal

Parameter

Fasting

Low-fat

High-fat

AUC0_¥ (ng/ml-h)

1,049 ± 420

1,891 ± 452*

2,015 ± 368*

Cmax (ng/ml)

196± 117

282±122*

278 ± 41*

Tmax (h)

2.1±1.0

3.1±1.5

4.1±2.1*

* Significantly different from fasted (ANOVA, p < 0.01)

* Significantly different from fasted (ANOVA, p < 0.01)

to decrease slowly to a baseline value of pH 1 after capsule administration. The range of gastric emptying times (GET) in the fasted state was 5-140 min, with a mean value of 60 min.

Compared to fasting, the low fat meal significantly (p < 0.01) increased the GET. The range of GET in dogs fed the low fat meal was 2.4-4.8 h with a mean of 4.2 h. The high fat meal also significantly increased (p < 0.01) the GET to a value of 7.4 h. The GET after the high fat meal was significantly longer than the GET value after the low fat meal (p < 0.01).

The GET of the Heidelberg capsule in humans fed a similar high-fat breakfast was 4.8 h [18]. It is not obvious why in the dog the low fat meal delayed gastric emptying to a similar extent as the standard high fat breakfast delayed gastric emptying in humans. Since fat content in meals has been reported as a major factor for gastric emptying in the dog [19], perhaps the dog required an extraordinary amount of time to digest such meals: once the fat had been digested, gastric emptying of the Heidelberg capsule occurred.

For the pharmacokinetic portion of the study, one capsule containing the commercial blend of 40 mg ziprasidone HCl was administered, followed immediately by an oral gavage of 50 ml of tap water. The peak plasma concentration (C ), time to peak plasma concentration (T ), and area under the plasma con-

centration/time curve (AUC0-¥) for dogs administered ziprasidone HCl under fasted and fed conditions are listed in Table 4.2. The presence of food increased the average plasma ziprasidone concentration in dogs (Fig. 4.1). Interestingly, both high and low fat meals produced a significant (p < 0.01) increase in AUC0-¥.

Time (hours)

Fig. 4.1 Average ziprasidone concentrations in dogs after a single dose of ziprasidone HCl capsules under fasting, low-fat and high-fat fed conditions

Time (hours)

Fig. 4.1 Average ziprasidone concentrations in dogs after a single dose of ziprasidone HCl capsules under fasting, low-fat and high-fat fed conditions

Fig. 4.2 Average ziprasidone concentrations in humans after a single dose of ziprasidone HCl capsules under fasting and high-fat breakfast conditions [20]

Fig. 4.2 Average ziprasidone concentrations in humans after a single dose of ziprasidone HCl capsules under fasting and high-fat breakfast conditions [20]

A similar food interaction was reported for ziprasidone in healthy volunteers [20]. In that study, the standard high fat breakfast caused a statistically significant increase in AUC0-¥ following 20 mg ziprasidone (1.7-fold, Fig. 4.2). Ziprasidone is a lipophilic drug with a clogP of 3.6 [21]. Increased exposure to lipophilic drugs administered with a meal has been frequently reported [22]. This observation has been explained by:

• Increased bile flow

• Prolonged gastric emptying in response to the meal

Bile contains bile salt and lecithin, which may improve solubilization of lipophilic compounds in fatty food contents, leading to more complete absorption [23].

The pharmacokinetics of investigational drugs is often determined in dogs during the preclinical phase of development to predict whether a food effect might be present. In canine studies, the low-fat meal apparently provided sufficient stimulus for increased bile flow, leading to enhanced drug absorption. Interestingly, a sham meal causes little bile secretion in humans but stimulates a 30% increase in bile secretion in dogs [24]. The dog also secretes a significantly larger volume of bile/day and greater amounts of bile salts than humans [5]. These differences may explain why a low fat meal in dogs mimicked the positive food effect in humans following a high fat meal.

In summary, because of the similar GET and apparent solubilizing affects, the low fat meal described, or a scaled version of the blended FDA high-fat breakfast may be the preferred meals for canine studies designed to predict a food effect in the clinic [109]. However, until additional studies have been published, it is uncertain how universally this recommendation may apply to various formulations and other lipophillic compounds.

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