Abstract
In the present work, we explored if Coca-Cola® had a beneficial impact on the systemic outcome of the weakly basic drug loratadine (Wal-itin®, immediate-release formulation, 10 mg, generic drug product). To map the contribution of underlying physiological variables that may positively impact the intestinal absorption of loratadine, a multi-compartmental and dynamic dissolution device was built, namely the Gastrointestinal Simulator (GIS). The luminal behavior of one immediate-release (IR) tablet of 10 mg of loratadine was tested under four different fasted state test conditions in the GIS: (i) with 250 mL of water and applying a predetermined gastric half-life (t1/2,G) of 15 min; (ii) with 250 mL of water and applying a t1/2,G of 30 min; (iii) with 250 mL of Coca-Cola® and a t1/2,G of 15 min; (iv) with 250 mL of Coca-Cola® and a t1/2,G of 30 min. After initiating the experiments, solution concentrations and solubility were measured in the withdrawn samples, and pH was monitored. To address the impact of the present CO2 in Coca-Cola® on the disintegration time of the tablet, additional disintegration experiments were performed in a single-vessel applying tap water and sparkling water as dissolution media. These experiments demonstrated the faster disintegration of the tablet in the presence of sparkling water, as the present CO2 facilitates the release of the drug. The buffer capacity of Coca-Cola® in the presence of FaSSGF was 4-fold higher than the buffer capacity of tap water in the presence of FaSSGF. After performing the in vitro experiments, the obtained results were used as input for a two-compartmental pharmacokinetic (PK) modeling approach to predict the systemic concentrations. These simulations pointed out that (i) the present CO2 in Coca-Cola® is responsible for the enhancement in drug release and dissolution and that (ii) a delay in gastric emptying rate will sustain the supersaturated concentrations of loratadine in the intestinal regions of the GI tract, resulting in an enhanced driving force for intestinal absorption. Therefore, co-administration of loratadine with Coca-Cola® will highly likely result in an increased systemic exposure compared to co-administration of loratadine with tap water. The mechanistic insights that were obtained from this work will serve as a scientific basis to evaluate the impact of Coca-Cola® on the systemic exposure of weakly basic drugs for patients on acid-reducing agents in future work.
Highlights
During the late stages of oral drug product development, bioequivalence studies are performed to confirm the efficacy and safety of the tested product before marketing
Current U.S Food & Drug Administration (FDA) bioequivalence guidelines promulgate co-administration of 240 mL of water to test the performance of the drug under fasted state conditions, whereas guidelines issued by the European Medicines Agency (EMA) indicate the administration of at least 150 mL of liquid to reflect fasting state conditions
Loratadine is categorized as a Biopharmaceutics Classification System 2b compound (BCS class 2b; weak base) with an estimated basic pKa of 3.83 and a predicted cLogP of 4.54 using the ADMET Predictor 9.5 (Simulations PlusTM, Lancaster, CA, USA)
Summary
During the late stages of oral drug product development, bioequivalence studies are performed to confirm the efficacy and safety of the tested product before marketing. Current U.S Food & Drug Administration (FDA) bioequivalence guidelines promulgate co-administration of 240 mL of water to test the performance of the drug under fasted state conditions, whereas guidelines issued by the European Medicines Agency (EMA) indicate the administration of at least 150 mL of liquid to reflect fasting state conditions. In Japan, oral drug products are tested with 150 mL of water in clinical studies, according to the guideline of the Pharmaceuticals and Medical Devices Agency (PDMA) [1,2,3]. A recent survey study revealed that 895 adults (16 years and older), living in Flanders, Belgium, took their medication with a sip or half glass of water [4]. It should be noted that patients were able to indicate more than one specific beverage
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