Vonoprazan

Vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H+, K+-ATPase enzyme system in a potassium competitive manner. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, vonoprazan has been characterized as a type of gastric proton-pump inhibitor, in that it blocks the final step of acid production. Vonoprazan does not require activation by acid. Vonoprazan may selectively concentrate in the parietal cells in both the resting and stimulated states. Vonoprazan binds to the active pumps in a noncovalent and reversible manner.

Antisecretory Activity

Following a single 10 mg or 20 mg dose of vonoprazan, the onset of the antisecretory effect as measured by intragastric pH occurs within 2 to 3 hours. The elevated intragastric pH levels compared to placebo increase with dose and are maintained for over 24 hours after dosing. The inhibitory effect of vonoprazan on acid secretion increases with repeated daily dosing and steady state is achieved by Day 4. The antisecretory effect of vonoprazan decreases following drug discontinuation although intragastric pH remained elevated compared to placebo for 24 to 48 hours following the dose on Day 7.

The effects of vonoprazan 10 mg or 20 mg once daily for 7 days on 24-hour intragastric pH in healthy subjects are shown in the following table.

Effect of Vonoprazan 10 mg or 20 mg Once Daily on 24-Hour Intragastric pH at Baseline and on Days 1 and 7 in Healthy Subjects:

Cardiac Electrophysiology

At a single dose of 120 mg (6-times the maximum recommended dose), vonoprazan does not prolong the QT interval to any clinically relevant extent.

Serum Gastrin Effects

The effect of vonoprazan on serum gastrin concentrations was evaluated in 514 patients for up to 8 weeks (healing phase) and in 592 patients for up to 6 months (maintenance phase). During the healing phase, the mean fasting gastrin levels at Week 2 increased from baseline after treatment with vonoprazan 20 mg and levels were similar at Week 2 and Week 8. In the 6-month maintenance phase, the mean gastrin levels remained elevated with vonoprazan 10 mg and 20 mg and the mean serum gastrin levels returned to normal within 4 weeks of discontinuation of treatment.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Enterochromaffin-Like Cell (ECL) Effects

Human gastric biopsy specimens were obtained from 135 patients treated with vonoprazan 10 mg or 20 mg once daily for up to 260 weeks. An increase in the incidence of hyperplasia of the parietal cells and G-cells was observed, which is consistent with the pharmacological action of a potassium-competitive acid blocker. No neoplastic changes were observed.

Steady state pharmacokinetic (PK) parameters for vonoprazan 10 mg or 20 mg following once daily administration and vonoprazan 20 mg following twice daily administration from data collected across multiple studies are summarized in Table 11.

Table 11. Mean (%CV) Steady State Pharmacokinetic Parameters For Vonoprazan Following Once or Twice Daily Dosing:

C_max = Maximum plasma concentration; AUC_0-24h = Area under the plasma concentration-time curve from time 0 to end of the 24-hour dosing interval; AUC_0-12h = Area under the plasma concentration-time curve from time 0 to the end of the 12-hour dosing interval; T_max = Time to reach C_max, t_1/2 = Elimination half-life, CL/F = Apparent oral clearance, V_z/F = Apparent oral volume of distribution
^* AUC_0-24h
^† AUC_0-12h

Absorption

Vonoprazan exhibits time independent pharmacokinetics and steady state concentrations are achieved by Day 3 to 4. After multiple doses of vonoprazan ranging from 10 to 40 mg (twice the maximum recommended dose) once daily for 7 days in healthy subjects, C_max and area under the plasma concentration time curve (AUC) values for vonoprazan increased in an approximately dose-proportional manner.

There is little accumulation in plasma after once daily multiple doses, with an accumulation index ratio of less than 1.2 based on AUC for doses ranging from 10 to 40 mg (twice the maximum recommended dose).

Steady state plasma exposure of vonoprazan following 20 mg twice daily dosing (AUC_0-12h = 273 hr*ng/mL, N=10) was approximately 1.8-fold higher compared to the mean estimate from the same subjects on Day 1 (AUC_0-12h = 155 hr*ng/mL, N=10).

Effect of Food

In a food effect study in healthy subjects (N=24) who received vonoprazan 20 mg, a high-fat meal resulted in a 5% increase in C_max, a 15% increase in AUC, and a delay in median T_max of 2 hours. These changes are not considered to be clinically significant.

Distribution

Plasma protein binding of vonoprazan ranged from 85 to 88% in healthy subjects and was independent of concentration from 0.1 to 10 mcg/mL.

Elimination

Metabolism

Vonoprazan is metabolized to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoforms (CYP3A4/5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6) along with sulfo- and glucuronosyl-transferases. CYP2C19 polymorphisms have been evaluated in clinical studies and there were no considerable differences in the pharmacokinetics of vonoprazan based on CYP2C19 metabolizer status.

Excretion

Following oral administration of radiolabeled vonoprazan, approximately 67% of the radiolabeled dose (8% as unchanged vonoprazan) was recovered in urine and 31% (1.4% as unchanged vonoprazan) was recovered in feces.

Specific Populations

Geriatric Patients

No clinically meaningful differences in the pharmacokinetics of vonoprazan are predicted in patients 65 years of age and older compared to younger adult patients.

Sex, Race or Ethnicity

There were no clinically significant differences in the pharmacokinetics of vonoprazan based on sex or race/ethnicity.

Patients with Renal impairment

The pharmacokinetics of vonoprazan administered as a single 20 mg dose in patients with mild [eGFR 60 to <90 mL/min/1.73m² (N=8)], moderate [eGFR 30 to <60 mL/min/1.73m² (N=8)], or severe [eGFR 15 to <30 mL/min/1.73m² (N=8)] renal impairment were compared to those with normal renal function [eGFR ≥90 mL/min/1.73m² (N=13)]. Compared to subjects with normal renal function, systemic exposure (AUC_0-inf) was 1.7-, 1.3-, and 2.4-times greater in patients with mild, moderate, and severe renal impairment, respectively. In subjects requiring dialysis (N=8), AUC_0-inf estimates were 1.3-fold greater compared to estimates from subjects with normal renal function. Protein binding of vonoprazan is not affected by impaired renal function. In patients requiring dialysis, vonoprazan was present in the dialysate and represented 0.94% of the dose administered.

Patients with Hepatic Impairment

The pharmacokinetics of vonoprazan administered as a single 20 mg dose in patients with mild [Child-Pugh Class A (N=8)], moderate [Child-Pugh Class B (N=8)], or severe [Child-Pugh Class C (N=6)] hepatic impairment were compared to those with normal hepatic function (N=12). Compared to subjects with normal hepatic function, systemic exposure (AUC_0-inf) of vonoprazan was 1.2-, 2.4-, and 2.6-times greater in patients with mild, moderate, and severe hepatic impairment, respectively. Protein binding of vonoprazan is not affected by impaired hepatic function.

Drug Interaction Studies

In Vitro Studies

Cytochrome P450 (CYP450) Enzymes:

In vitro studies have shown that vonoprazan directly and time-dependently inhibits CYP2B6, CYP2C19, and CYP3A4/5.

Transporter Systems:

Vonoprazan inhibits multidrug and toxin extrusion protein 1 (MATE1) and organic cation transporter 1 (OCT1), but only at concentrations higher than clinically relevant.

Clinical Studies

Combination Therapy with Vonoprazan, Amoxicillin, and Clarithromycin:

When vonoprazan 20 mg, amoxicillin 750 mg and clarithromycin 400 mg were co-administered twice daily for 7 days (N=11), there was no effect on pharmacokinetics of amoxicillin compared to amoxicillin alone. However, vonoprazan C_max and AUC_0-12h increased by 87% and 85%, respectively, and clarithromycin C_max and AUC_0-12h increased by 64% and 45% respectively, compared to administration of each component alone.

Effect of Vonoprazan on CYP3A4 Substrates:

When a single oral dose of midazolam 2 mg was administered following vonoprazan 20 mg twice daily for 7 days (N=20), midazolam AUC_0-inf increased 93% compared to administration of midazolam alone.

Effect of CYP3A Inhibitors on Vonoprazan:

When a single dose of 40 mg vonoprazan (twice the maximum recommended dose) was administered with clarithromycin 500 mg twice daily for 7 days (N=16), vonoprazan AUC_0-inf increased 58% compared to administration of vonoprazan alone.

Coadministration of Vonoprazan with NSAIDs or Low Dose Aspirin:

When a single dose of 40 mg vonoprazan (twice the maximum recommended dose) was co-administered with diclofenac 25 mg, meloxicam 10 mg, or aspirin 100 mg, there were no clinically meaningful changes in exposure of vonoprazan, diclofenac, meloxicam, or aspirin compared to administration of each drug alone.

Model-Informed Approaches

Effect of CYP3A Inducers on Vonoprazan:

Vonoprazan exposures are predicted to be 80% lower when co-administered with a strong CYP3A4 inducer such as rifampicin and 50% lower when co-administered with a moderate CYP3A4 inducer such as efavirenz.

Animal Toxicology and/or Pharmacology

During lifetime exposure of mice and rats dosed daily with up to 200 mg/kg/day and 150 mg/kg/day of vonoprazan respectively, increases in gastrin levels and marked neuroendocrine hyperplasia and gastropathy were observed followed by formation of carcinoid tumors. This finding is considered to be a rodent-specific phenomenon.