Proof of Concept Mimicking the Performance of a Gastric Retentive Formulation

It is relatively simple to determine the potential benefit of a GRF without actually designing a dosage form. An excellent literature example of this type of clinical study was performed using Acyclovir by Lewis et al. [5] as shown in Fig. 17.2. Lewis found that use of a simple "sipping" method was extremely beneficial. These investigators dosed 400 mg of acyclovir via an oral immediate release tablet (2 x 200 mg tablets), a duodenal infusion (500 mL of a 5% dextrose solution, constant infusion rate over 4 h) and a "sipped solution" (10.4 mL of the 500 mL 5% dextrose solution every 5 min over 4 h). Both the duodenal infusion and "sipping" methods provided AUCs almost twice that of the tablets. The sipping technique is an extremely simple and cost-effective approach to determine if saturable transport is limiting bioavailability.

In addition to investigating a specific mechanism that is resulting in reduced exposure, this technique can be used to generate drug release rates similar to what would be expected from a GRF. In Fig. 17.3, a single IR tablet was compared to eight sequential doses of 1/8 the total IR dose over a 4-h period [6]. In this case, the AUC increased by 27% indicating a benefit in pursuing a gastroretentive formulation. In both cases, an appropriate clinical study design generated clear data to determine if a gastric retentive dosage form would be worth pursuing.

Fig. 17.2 Effect of administration rate of acyclovir on its plasma concentration profile in healthy volunteers. 400 mg dose administered either as 2 x 200 mg tablets at one time, or sipped as a solution every 5 min over a 4-h period [5]

Fig. 17.2 Effect of administration rate of acyclovir on its plasma concentration profile in healthy volunteers. 400 mg dose administered either as 2 x 200 mg tablets at one time, or sipped as a solution every 5 min over a 4-h period [5]

Fig. 17.3 Effect of providing eight sequential doses of 12.5 mg each over 4 h versus a single dose of 172 mg on the plasma profile of a GSK Compound [6]

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