Vocinti Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Vonoprazan is a potassium competitive acid blocker (PCAB) and inhibits H⁺, K⁺-ATPase in a reversible and potassium-competitive manner. It does not require activation by acid. 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 the upper part of the gastrointestinal tract. Vonoprazan does not exhibit anti-Helicobacter pylori activity nor inhibitory activity against Helicobacter pylori urease.
Serum Gastrin and Serum Pepsinogen Effects: Increased serum gastrin and serum pepsinogen concentrations are physiological responses to treatment with acid suppression therapy, including vonoprazan. Increased serum gastrin and serum pepsinogen concentrations were reported with a higher incidence in the vonoprazan treatment groups compared with lansoprazole treatment groups. Serum gastrin and serum pepsinogen concentrations returned to baseline over time upon discontinuation of vonoprazan. The increase in serum gastrin concentration occurred early in treatment with vonoprazan and remained stable for the remainder of treatment.
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.
Clinical Studies: Clinical efficacy: (1) Gastric ulcer, duodenal ulcer: The following table shows the overall healing rate by disease category of patients with gastric ulcer and duodenal ulcer who received a once daily oral dose of 20 mg of vonoprazan or 30 mg of lansoprazole for up to 8 weeks (in the case of gastric ulcer) and 6 weeks (in the case of duodenal ulcer) in double-blind comparative controlled studies. From the study conducted in patients with gastric ulcer, the non-inferiority was verified in the vonoprazan group compared to the lansoprazole group, however, the non-inferiority was not verified in the vonoprazan group compared to the lansoprazole group in the study in patients with duodenal ulcer. (See Tables 2 and 3.)


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(2) Reflux esophagitis: The following table shows the overall healing rate until 4 and 8 weeks after administration in patients with reflux esophagitis who received a once daily oral dose of 20 mg of vonoprazan or 30 mg of lansoprazole for up to 8 weeks in double-blind comparative controlled study. The non-inferiority was verified in the vonoprazan group compared to the lansoprazole group for the healing rate up to 8 weeks after administration. In addition, the point estimate (two-sided 95% confidence interval) of a difference between the healing rate until 4 weeks after administration in the vonoprazan group and the healing rate until 8weeks after administration in the lansoprazole group was 1.1% (-2.702 to 4.918%). (See Tables 4 and 5.)


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(3) Maintenance therapy of reflux esophagitis: 1) The recurrence rate observed in the single-blind long-term study in which a daily dose of 10 mg or 20 mg of vonoprazan was administered once daily for 52 weeks to the patients with confirmed healing of the reflux esophagitis and completed the study described in (2) above was 9.4% (14/149 cases) in the 10 mg group and 9.0% (13/145 cases) in the 20 mg group.
2) The following table shows the recurrence rate observed in the double-blind comparative controlled study in which a daily oral dose of 10 mg or 20 mg of vonoprazan or 15 mg of lansoprazole was administered once daily for 24 weeks in the maintenance of healing to patients with reflux esophagitis that was assessed as "healed" as the result of oral administration of a daily dose of 20 mg of vonoprazan once daily up to 8 weeks. The non-inferiority was verified in the vonoprazan 10 mg and 20 mg groups compared to the lansoprazole group. (See Table 6.)


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(4) Prevention of recurrence of gastric ulcer or duodenal ulcer during low-dose aspirin administration: The following table shows the ulcer recurrence rate at 24 weeks after a once daily oral dose of 10 mg of vonoprazan or 15 mg of lansoprazole was administered once daily for 24 weeks to patients who required long-term low-dose aspirin administration (daily dose of 81 to 324 mg) and had a history of gastric ulcer or duodenal ulcer in double-blind comparative controlled study. The non-inferiority was verified in the vonoprazan group compared to the lansoprazole group. (See Table 7.)


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The following table shows the ulcer recurrence rate observed in the single-blind long-term study in which administration was continued for 28 weeks in minimum and for 80 weeks at maximum to the patients who completed the above study. (See Table 8.)


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(5) Prevention of recurrence of gastric ulcer or duodenal ulcer during NSAIDs administration: The following table shows the ulcer recurrence rate at 24 weeks after a once daily oral dose of 10 mg of vonoprazan or 15 mg of lansoprazole was administered once daily for 24 weeks to patients who required long-term administration of NSAIDs for pain management of rheumatoid arthritis or osteoarthritis, etc. and had a history of gastric ulcer or duodenal ulcer in double-blind comparative controlled study. The non-inferiority was verified in the vonoprazan group compared to the lansoprazole group. (See Table 9.)


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The following table shows the ulcer recurrence rate observed in the single-blind long-term study in which administration was continued for 28 weeks in minimum and for 80 weeks at maximum to the patients who completed the above study. (See Table 10.)


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(6) Helicobacter pylori infection in gastric ulcer or duodenal ulcer: The following table shows the eradication rates in Helicobacter pylori-positive gastric ulcer or duodenal ulcer scar patients who were administered with the following 3 drugs, i.e., 20 mg of vonoprazan or 30 mg of lansoprazole, amoxicillin hydrate, and clarithromycin, twice daily for 7 days in double-blind comparative controlled study. The non-inferiority was verified in triple therapy using vonoprazan compared to triple therapy using lansoprazole. (See Table 11.)


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In addition, the following table shows the eradication rates observed in the clinical trial in which 50 patients for whom Helicobacter pylori eradication with vonoprazan or lansoprazole, amoxicillin hydrate, and clarithromycin failed received oral administration of 20 mg/dose of vonoprazan, amoxicillin hydrate, and metronidazole twice daily for 7 days. (See Table 12.)


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Effects on serum gastrin and density of endocrine cells in gastric mucosa: (1) After a once daily oral administration of 10 mg or 20 mg of vonoprazan, serum gastrin levels were continuously higher in the vonoprazan group compared to the lansoprazole group. The changes in serum gastrin levels in a long-term clinical study for prevention of gastric ulcer or duodenal ulcer with administration of low dose aspirin is as shown as follows. The clinical trial in which patients with gastric ulcer and those with duodenal ulcer were evaluated for recovery of serum gastrin after the termination of administration observed the rapid recovery. (2 - 8 weeks after completion of administration.) (See Figure 1.)


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(2) When a once daily oral dose of 10 mg or 20 mg of vonoprazan was administered for 52 weeks in the maintenance of healing of reflux esophagitis, no obvious tendency toward an increase in the density of endocrine cells in gastric mucosa was observed.
Pharmacokinetics: Absorption: (a) Pharmacokinetics at single administration: Absolute bioavailability has not been determined. The pharmacokinetic parameters of vonoprazan following single administration of vonoprazan to healthy adult male subjects at 20 mg under fasting and fed conditions are presented in the following table (see Table 13 and Figure 2).


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(b) 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_½ of vonoprazan. The following table shows pharmacokinetic parameters of vonoprazan on day 7 of administration. (See Table 14.)


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Distribution: The mean 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: (1) 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).
(2) 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 (15 mg 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.
Impaired Renal Function: The effect of renal disorders on pharmacokinetics of vonoprazan in subjects with normal renal function, patients with mild, moderate, and severe renal disorder and patients with end-stage renal disease (ESRD) 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, showing an increase with a reduction in 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.
Impaired Hepatic disorders: The effect of hepatic disorders on phannacokinetics in subjects with normal hepatic function and patients with mild, moderate, and severe hepatic disorder when administered 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 patients with mild, moderate, and severe hepatic disorder, compared to subjects with normal hepatic function.
Age, Gender, Race: Vonoprazan has not been studied in patients under 18 years of age. There are no clinically relevant gender effects of vonoprazan. No dedicated ethnic comparison studies have been conducted with vonoprazan. The ethnic sensitivity analysis based on the International Conference for Harmonization (ICH) E5 principles was conducted to assess whether the molecular properties of vonoprazan were sensitive to ethnic factor differences, and whether the diagnosis, medical practice, treatment options, and other epidemiological factors for acid-related disorders would vary dramatically in areas other than Japan. It was concluded that vonoprazan is insensitive to ethnic factor differences.
Drug Interactions: (1) 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 40 mg 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.
(2) 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 by 1.5 times and 1.6 times, respectively.
(3) Vonoprazan, Bismuth, Clarithromycin and Amoxicillin: The drug interaction study in Helicobacter pylori positive adult subjects administered twice daily vonoprazan 20 mg or lansoprazole 30 mg with tripotassium bismuth dicitrate 600 mg, clarithromycin 500 mg, and amoxicillin 1000 mg concomitantly for 14 days shows the lack of a clinically meaningful effect of vonoprazan on the pharmacokinetics of bismuth compared with lansoprazole.
(4) Vonoprazan, amoxicillin hydrate and metronidazole: The drug interaction study in healthy adult male subjects administered twice daily with vonoprazan 20 mg, amoxicillin hydrate 750 mg (potency) and metronidazole 250 mg concomitantly for 7 days showed little difference in the pharmacokinetics of vonoprazan, when administered alone or as triple therapy. No difference was observed in the pharmacokinetics of metronidazole or amoxicillin when administered alone or as triple therapy.
(5) 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 60 mg, diclofenec 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.