Pharmacology: Mechanism of action: Vonoprazan does not require activation by acid and inhibits H
+, K
+-ATPase in a reversible and potassium-competitive manner. Vonoprazan has a strong basicity and resides on the acid production site of gastric parietal cells for a long time, thereby inhibiting gastric acid production. Vonoprazan exerts a strong inhibitory effect on formation of mucosal damage in upper part of the gastrointestinal tract. Vonoprazan does not exhibit anti-
Helicobacter pylori activity nor inhibitory activity against
Helicobacter pylori ureas.
Inhibiting activity on gastric acid secretion: Following consecutive administration of Vonoprazan at a dose of 10 mg or 20 mg in healthy adult male subjects for 7 days, proportions of the time exhibiting gastric pH of 4 or above within 24 hours were 63±9% and 83±17%, respectively.
Adjunctive effect on eradication of Helicobacter pylori: The role of Vonoprazan in the
Helicobacter pylori eradication is considered to increase intragastric pH leading to the enhancement of antibacterial activity of amoxicillin hydrate, clarithromycin and metronidazole which are concomitantly administered.
Pharmacokinetics: Absorption: Effect of Foods: The following table shows pharmacokinetic parameters of Vonoprazan following single administration of Vonoprazan to healthy adult male subjects at 20 mg under fasting and after meal. Effect of food on pharmacokinetic was little observed. (See Table 1 and figure.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Blood level: Pharmacokinetics at consecutive administration: At consecutive administration of a daily dose of 10 mg or 20 mg of Vonoprazan in healthy adult male subjects once daily for 7 days, AUC
(0-tau) and C
max increase as the dose increases. The degree of these increases is slightly higher than the dose ratio. It is considered that the steady state has been reached by day 3 of administration, since the trough level of the blood concentration of Vonoprazan is constant between day 3 and day 7 of administration. In addition, it is considered that pharmacokinetics of Vonoprazan at consecutive administration may not be time-dependent, as the result of the evaluation of accumulation with regard to AUC
(0-tau) and T
1/2 of Vonoprazan. The following table shows pharmacokinetic parameters of Vonoprazan on day 7 of administration. (See Table 2.)
Click on icon to see table/diagram/image
Distribution: Protein binding rate: The protein binding rate is 85.2 to 88.0% when [
14C] Vonoprazan in the range of 0.1 to 10 μg/mL is added to human plasma (
in vitro).
Metabolism: Vonoprazan is metabolized mainly by hepatic drug-metabolizing enzyme CYP3A4 and partially by CYP2B6, CYP2C19 and CYP2D6. Vonoprazan is also metabolized by sulfotransferase SULT2A1 (
in vitro).
Vonoprazan exhibits time-dependent inhibitory effect on CYP2B6, CYP2C19 and CYP3A4/5 (
in vitro). In addition, Vonoprazan shows a slight concentration-dependent inductive effect on CYP1A2, but it shows little inductive effect on CYP2B6 and CYP3A4/5 (
in vitro).
Excretion: When radioactive-labeled drug (15mg as Vonoprazan) is orally administered to non-Japanese healthy adult male subjects, 98.5% of the radioactivity administered is excreted into urine and feces by 168 hours after administration: 67.4% into urine and 31.1% into feces.
Patients with Specific Backgrounds: Pharmacokinetics in patients with hepatic disorders: The clinical trial conducted in abroad to evaluate the effect of hepatic disorders or pharmacokinetics in subjects with normal hepatic function and patients with mild (Child-Pugh score: A), moderate (Child-Pugh score: B), and severe (Child-Pugh score: C) hepatic disorder when administered with the drug as Vonoprazan 20 mg shows that AUC
(0-inf) and C
max were higher by 1.2 to 2.6 times and 1.2 to 1.8 times, respectively, in patient with mild, moderate and severe hepatic disorder, compared to subjects with normal hepatic function.
Pharmacokinetics in patients with renal disorders: The clinical trial conducted in abroad to evaluate the effect of renal disorders on pharmacokinetics of Vonoprazan in subjects with normal renal function (eGFR: ≥90 mL/min/1.73m
2), patients with mild (eGFR: 60-89 mL/min/1.73m
2), moderate (eGFR: 30-59 mL/min/1.73m
2), and severe (eGFR: 15-29 mL/min/1.73m
2) renal disorder and patients with end-stage renal disease (ESRD) (eGFR: <15 mL/min/1.73m
2) when administered the drug as Vonoprazan 20 mg shows that AUC
(0-inf) and C
max were higher by 1.3 to 2.4 times and 1.2 to 1.8 times, respectively, in patients with mild, moderate and severe renal disorder compared to subjects with normal renal function. AUC
(0-inf) and C
max were higher by 1.3 times and 1.2 times, respectively, in ESRD patients compared to those in subjects with normal renal function.
Drug Interactions: Pharmacokinetics at concomitant administration of Vonoprazan and clarithromycin: The drug interaction study in non-Japanese healthy adult male subjects administered with single dose of Vonoprazan 40mg 30 minutes after breakfast on day 1 and day 8, and with repeated dose of clarithromycin 500 mg (potency) 2 times daily 30 minutes before breakfast and dinner on day 3-9, shows that AUC
(0-inf) and C
max of Vonoprazan when concomitantly administered with clarithromycin increased by 1.6 times and 1.4 times, respectively, compared to those of Vonoprazan when administered alone.
Pharmacokinetics at concomitant administration of Vonoprazan, amoxicillin hydrate and clarithromycin: The drug interaction study in healthy adult male subjects administered with twice daily of Vonoprazan 20 mg, amoxicillin hydrate 750 mg (potency) and clarithromycin 400 mg (potency) concomitantly for 7 days shows that no effect on pharmacokinetics of unchanged amoxicillin, however, AUC
(0-12) and C
max of Vonoprazan increased by 1.8 times and 1.9 times, respectively, and AUC
(0-12) and C
max of unchanged clarithromycin increased 1.5 times and 1.6 times, respectively.
Pharmacokinetics at concomitant administration of vonoprazan, low-dose aspirin or Vonoprazan, NSAIDs: The drug interaction study in healthy adult male subjects administered with Vonoprazan 40 mg and aspirin 100 mg or NSAID (loxoprofen sodium 60mg, diclofenac sodium 25 mg or meloxicam 10 mg) concomitantly showed no clear effect of low-dose aspirin or NSAIDs on pharmacokinetics of Vonoprazan and of Vonoprazan on pharmacokinetics of low-dose aspirin or NSAIDs.