ABSTRACT
PURPOSE: A fixed-dose combination (FDC) of proton pump inhibitors (PPIs) and antacid salts enables rapid acid suppression through the neutralizing effect of the antacid salt and the rapid absorption of PPIs. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a recently formulated FDC of esomeprazole and magnesium hydroxide to the enteric-coated esomeprazole in healthy subjects. METHODS: A randomized, open-label, multiple-dose, two-treatment, two-way crossover design was conducted in healthy subjects. Forty-nine subjects were randomized to one of the two treatment sequences and received either the test drug (esomeprazole/magnesium hydroxide 40/350 mg) or reference drug (enteric-coated esomeprazole 40 mg) for 7 days in the first period and the alternative in the second period with a 14-day washout period. Blood samples were collected for up to 24 hours for PK assessment, and 24-hour gastric pH monitoring was conducted for PD assessment both before and after a single administration, as well as at a steady state after seven consecutive days of administration. The PK and PD parameters were compared between the two drugs. FINDINGS: After multiple administrations, the median value of time to reach maximum concentration was faster in the test drug than in the reference drug, with a difference of 1.68 hours. The overall systemic exposure of the test drug was similar to that of the reference drug, and the PK parameter fell within the equivalence criteria. The test drug demonstrated a shorter time to reach gastric pH ≥ 4 compared to the reference drug (P = 0.0463). A decrease from baseline in integrated gastric acidity over 24 hours, which represents the degree of inhibition of gastric acid secretion, was equivalent between the two drugs. IMPLICATIONS: The fixed-dose combination of esomeprazole and magnesium hydroxide showed rapid absorption and quicker gastric acid suppression than enteric-coated esomeprazole with comparable PK and PD properties. CLINICALTRIALS: gov identifier: NCT04324905 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04324905).
ABSTRACT
Compared to pelubiprofen, a cyclooxygenase-2-selective inhibitor, pelubiprofen tromethamine has been reported to exhibit improved solubility and absorption. Pelubiprofen tromethamine combines the anti-inflammatory effect of pelubiprofen with the gastric protective function of tromethamine salt, making it a relatively safe class of non-steroidal anti-inflammatory drugs with low levels of gastrointestinal side effects in addition to its original analgesic, anti-inflammatory, and antipyretic effects. This study assessed the pharmacokinetic and pharmacodynamic characteristics of pelubiprofen and pelubiprofen tromethamine in healthy subjects. Two independent clinical trials were performed in healthy subjects using a randomized, open-label, oral, single-dose, two-sequence, four-period, crossover design. In Study I and Study II, subjects received 25 mg of pelubiprofen tromethamine and 30 mg of pelubiprofen tromethamine, respectively, with 30 mg of pelubiprofen being the reference. Study I fell within the bioequivalence study criteria. A trend of increased absorption and exposure for 30 mg of pelubiprofen tromethamine vs. the reference in Study II was observed. The maximum cyclooxygenase-2 inhibitory effect of 25 mg of pelubiprofen tromethamine was approximately 98% compared to the reference, showing no significant pharmacodynamic variation. It is thus predicted that 25 mg of pelubiprofen tromethamine would show no clinically significant discrepancies in clinical analgesic and antipyretic effects from 30 mg of pelubiprofen.
ABSTRACT
Purpose: Proton pump inhibitors (PPIs) are the first-line therapy for gastroesophageal reflux disorder (GERD). Unlike conventional PPIs, non-enteric coated PPIs with antacid salt enable a faster acid suppression through the rapid absorption of the PPI. YPI-011 is a newly developed fixed-dose combination of a rabeprazole with sodium bicarbonate (NaHCO3). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of YPI-011 to the conventional enteric-coated rabeprazole (Pariet®). Materials and Methods: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with two different doses (10 and 20 mg) and 44 subjects in each group. They randomly received either a test or reference treatment for 7 days in the first period and the other treatment in the second period. Blood samples for the PK analysis were taken after the single- and multiple-dose. Intragastric pH monitoring for the PD analysis was implemented for baseline and after the single- and multiple-dose. Results: Gastric acid suppression evaluated by the percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the multiple-dose was similar between the treatments in both dose groups. The systemic exposure of rabeprazole at steady state after the multiple-dose was also similar between the treatments in both dose groups. The time to reach the maximum rabeprazole concentration was faster in the test treatment. The PK-PD relationship of PPI is well known, and the faster absorption of rabeprazole resulted in a more rapid mode of action in acid suppression. Conclusion: The fixed dose combination of rabeprazole with NaHCO3 showed a faster absorption and consequently, a more rapid gastric acid suppression with a similar systemic exposure of rabeprazole at steady state compared to the conventional enteric-coated rabeprazole.