Abstract
Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.
Highlights
Proton pump inhibitors (PPIs) are commonly prescribed as the first-line drug for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD) by inhibiting H+/K + -ATPase (Katz et al, 2013; Otake et al, 2016)
The major limitations are as follows: 1) PPIs are acid labile, 2) PPIs shows a slow onset of action, taking 3–5 days for the appropriate effect, 3) PPIs show interindividual variations in pharmacokinetics (PK) according to cytochrome P450 (CYP) 2C19, and 4) PPIs fail to suppress nocturnal acid secretion expected by the short half-life (Otake et al, 2016)
This study aimed to evaluate the PK of atorvastatin and safety profile when co-administered with Potassium-competitive acid blocker (P-CAB), vonoprazan or tegoprazan
Summary
Proton pump inhibitors (PPIs) are commonly prescribed as the first-line drug for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD) by inhibiting H+/K + -ATPase (Katz et al, 2013; Otake et al, 2016). The major limitations are as follows: 1) PPIs are acid labile, 2) PPIs shows a slow onset of action, taking 3–5 days for the appropriate effect, 3) PPIs show interindividual variations in pharmacokinetics (PK) according to cytochrome P450 (CYP) 2C19, and 4) PPIs fail to suppress nocturnal acid secretion expected by the short half-life (Otake et al, 2016). While PPIs require chemical conversion to their active form and only inhibit an activated form of H+/K + -ATPase, P-CAB does not require acid activation and reversely inhibits both an activated and inactivated form of H+/K + -ATPase by competitively blocking the potassium-binding site (Mori and Suzuki, 2019). P-CAB shows a rapid onset of acid suppression and continuous acid suppression until the night compared to PPIs (Okuyama et al, 2017; Mori and Suzuki, 2019; Cho et al, 2020)
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