Equine Gastric Ulcer Syndrome (EGUS) is a common condition of the horse, affecting a broad range of horse usages and types. Recently the terminology of the syndrome has been expanded to include terms Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD) to describe diseases of the squamous and glandular mucosa of the stomach, respectively.
Omeprazole, a proton pump inhibitor that blocks acid production, is considered the treatment of choice for EGUS and it has been widely used for this purpose for nearly 20 years. Yet, surprisingly, despite its widespread use little is known about the factors that affect its efficacy, such as the impact of formulation, diet and dose. Further, although it is commonly believed that the once daily administration of omeprazole results in durations of acid suppression exceeding 24 hours, there is conflict in the literature as to the validity of this belief. Recent clinical studies have demonstrated that the healing rate for EGGD is inferior to that of ESGD, raising further questions as to the efficacy of omeprazole under clinically relevant conditions. One potential reason for this observation is that the duration of intra-day acid suppression required for healing of ESGD may be less than that for EGGD. This, coupled with the possibility that once daily administration of omeprazole may not result in acid suppression for the entire 24 hour treatment interval, provides a potential explanation for the poor EGGD healing rates that have been recently reported.
The purpose of this thesis was to investigate the factors that affect the efficacy of omeprazole in the horse. The studies were conducted in four parts; firstly, the effect of formulation and diet on the pharmacokinetics of omeprazole were investigated; secondly, a model that allows continuous intra-gastric pH measurement under clinically relevant conditions was developed; thirdly, the impact of diet and dose on the pharmacokinetics and pharmacodynamics of omeprazole were investigated; and lastly, the relationships between key pharmacokinetic and pharmacodynamic variables were investigated.
The findings of the study suggested that some method of physical protection is required to protect the omeprazole from degradation in the acidic environment of the stomach and to improve bioavailability. However, significant differences were not present between formulations utilising the two most common forms of protection, namely the use of enteric coated granules in paste or buffering of the formulation. This suggests that the method of protection, buffering of the formulation or the use enteric coated granules in paste, used is less important than protection per se. The earlier studies of the thesis suggested that an effect of feeding may be present on the pharmacokinetics of omeprazole but a statistically significant effect could not be demonstrated. Similarly, the latter studies suggested that diet may play a role in bioavailability with ad libitum roughage diets impairing absorption, but no statistically significant effect was present. A wide degree of inter-individual variation was present and the small numbers of animals used may have meant that the power of the studies was inadequate to document such an effect. However, an effect of diet on the pharmacodynamics of omeprazole was present with a lower magnitude and duration of acid suppression consistently observed in ad libitum roughage diets when compared with high grain/low fibre diets. An inconsistent effect of dose on the pharmacodynamics of omeprazole was observed with the effect the most pronounced in the high grain/low fibre diet. In contrast, no effect of dose was present in the ad libitum roughage diet, although the overall efficacy of both doses was poor under these conditions. Lastly, the key pharmacokinetic and pharmacodynamic parameters correlated poorly, which suggested that plasma concentrations are poorly predictive of pharmacodynamic response in the horse, although the reasons for this are unclear as in other species area under the curve is predictive of pharmacodynamic response.
The results of the present studies suggested that both diet and dose impact on the pharmacodynamics of omeprazole in the horse. The overall low efficacy of omeprazole under the ad libitum roughage dietary conditions was surprising but potentially significant. Firstly, it provides a potential explanation for the poor healing rates recently reported for EGGD. Secondly, it suggests that singular dosing recommendations that encompass all horse types and usages, as currently used, may not be appropriate. Instead the use of dosing recommendations that take into account the diet and management of the horse may be advantageous. Lastly, the findings of the thesis demonstrate that further studies into alternative dosing regimens, such as higher dose or twice daily administration, or the investigation of alternative therapeutic agents are required to address the need a therapeutic approach that allows for effective acid suppressive therapy in horses on high roughage diets.