Factors affecting the pharmacokinetics and pharmacodynamics of omeprazole in the horse

Abstract

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 3 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 signi...

Evaluation of the treatment of equine glandular gastric disease with either long‐acting‐injectable or oral omeprazole

“…Whilst there is a widely held view that once daily administration of ORLO results in 24 hours of acid suppression based on early studies (Jenkins et al., 1992 ; Daurio et al., 1999 ), the average duration of acid suppression with oral treatment at 4 mg/kg was under 12 hours in one study (Merritt et al., 2003 ) and may be much lower in horses on a high forage diet (Sykes, 2016 ). In many animals the duration of acid suppression with ORLO may not be sufficient for EGGD healing, particularly in the pyloric region where pH is lowest.…”

A study investigating the treatment of equine squamous gastric disease with long‐acting injectable or oral omeprazole

“…When omeprazole is administered via an oral route, variation between horses may be compounded by differences in bioavailability which can vary up to 10‐fold (Sykes, Underwood, et al, ). Although initial reports indicated that oral omeprazole suppressed acid production for the 24‐hr period between doses (Daurio et al, ; Jenkins et al, ), more recent studies suggest that for at least half the 24‐hr treatment interval there may be insufficient acid suppression to promote healing of the squamous mucosa (Merritt, Sanchez, Burrow, Church, & Ludzia, ), particularly in horses that are fed a high forage diet (Sykes, ).…”

The effects of dose and diet on the pharmacokinetics of omeprazole in the horse

“…Another potential weakness is that the presence of the PEG tube and gastropexy may have altered gastric motility. The use of PEG‐instrumented horses allowed for the concurrent measurement of intragastric pH as part of separate studies investigated the pharmacodynamics of omeprazole in the horse (Sykes et al ., ). A potential effect of the PEG tube and gastropexy via alterations in gastric motility and emptying on the pharmacokinetics reported in this study cannot be completely discounted.…”