Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools

Abstract

This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated.

Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging†

“…The different gastric acidity in fasted and fed conditions might lead to differences in oral drug dissolution and the speed of precipitation within the gastrointestinal tract. [32] Correspondingly, the peak plasma concentration of diclofenac under fed conditions was reported to be significantly lower and the time to peak plasma concentration was significantly longer compared to fasted conditions. [23] The state of food intake was not standardized in our study, which might have altered absorption and bioavailability rates of diclofenac.…”

“…It has been reported that various physiological factors could contribute to interindividual differences in drug disposition after oral application. The different gastric acidity in fasted and fed conditions might lead to differences in oral drug dissolution and the speed of precipitation within the gastrointestinal tract . Correspondingly, the peak plasma concentration of diclofenac under fed conditions was reported to be significantly lower and the time to peak plasma concentration was significantly longer compared to fasted conditions .…”

In vitro methods to assess drug precipitation in the fasted small intestine – a PEARRL review

“…Recently, Van Den Abeele et al ., have used an updated version of TIM‐1 (TIMagc) with the aim of investigating the intraluminal behaviour of diclofenac in the fasted and fed state. The results obtained from the in vitro setup were compared with intraluminal and systemic data collected from healthy volunteers after the administration of diclofenac tablets along with 240 ml of water.…”

The impact of food intake on the luminal environment and performance of oral drug products with a view toin vitroandin silicosimulations: a PEARRL review

“…Delayed tablet disintegration played an important role. Similarly, Van den Abeele et al . studied the GI disposition of the IR tablet Cataflam ® (50 mg diclofenac potassium) administered with a liquid meal (Ensure ® plus).…”

“…Van den Abeele et al . (Table ) used Cataflam ® (50 mg diclofenac potassium) tablet in vivo data as a reference for the evaluation of in vitro tools with different levels of complexity, that is USP apparatus II in combination with biorelevant media, a modified dynamic open USP apparatus IV and the TIMagc, where fed state was simulated with Ensure ® Plus. The authors concluded that all three in vitro tools provided information on intraluminal or plasma concentrations in the fed state.…”