Abstract
Fexuprazan, a novel potassium‐competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti‐inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open‐label, multicenter, six‐sequence, one‐way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1–2 days in the second period. Serial blood samples for PK analysis were collected until 48‐ or 72‐h post‐dose at steady state. PK parameters including maximum plasma concentration at steady state (C max,ss) and area under plasma concentration–time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in C max, 19% in AUCτ,ss) were observed when co‐administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for C max,ss and AUCτ,ss was 1.22 (1.02–1.46) and 1.19 (1.00–1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Gastroprotective agents (i.e., proton pump inhibitors, H2 receptor antagonists, prostaglandin analogs) are likely to co‐prescribed with nonsteroidal anti‐inflammatory drugs (NSAIDs) to prevent NSAID‐induced peptic ulcer.
Fexuprazan, a novel potassium‐competitive acid blocker (P‐CAB), is expected to be used for the prevention of NSAID‐induced peptic ulcer by inhibiting gastric acid secretion.
WHAT QUESTION DID THIS STUDY ADDRESS?
This study comprehensively examined bidirectional pharmacokinetic (PK) drug–drug interactions (DDIs), assessing the effect of fexuprazan on the PKs of NSAIDs and conversely, evaluating the effect of NSAIDs on the PKs of fexuprazan in healthy male subjects.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The systemic exposure of fexuprazan was slightly increased by naproxen, indicating a weak DDI between fexuprazan and naproxen.
There are no clinically meaningful pharmacokinetic interactions between fexuprazan and three different NSAIDs (celecoxib, naproxen, and meloxicam).
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This study provided the clinical evidence of co‐administration of fexuprazan and NSAIDs for the prevention of NSAID‐induced peptic ulcer.
INTRODUCTION
Fexuprazan, a novel potassium‐competitive acid blocker (P‐CAB), is expected to be used for nonsteroidal anti‐inflammatory drugs (NSAIDs)‐induced peptic ulcers as an effective gastroprotective agent. Prolonged use of NSAIDs can lead to inhibition of prostaglandin synthesis, resulting in gastric wall injuries and the development of peptic ulcers, known as NSAID‐induced peptic ulcers. 1 Clinical guidelines recommend the co‐administration of gastroprotective agents such as proton pump inhibitors, H2 receptor antagonists, and prostaglandin analogs to prevent peptic ulcers in patients receiving long‐term NSAID treatment. 1 , 2 , 3 These agents are commonly prescribed along with NSAIDs for patients requiring long‐term management of conditions like rheumatoid arthritis. 4 , 5 , 6
Fexuprazan, a reversible inhibitor of the H+/K+‐ATPase enzyme, has been approved for the management of gastro‐esophageal reflux disease (GERD). 7 It demonstrates favorable pharmacokinetic (PK) properties, including rapid onset of action and prolonged elimination half‐life (7.5–9.5 h), which contributes to its effective and sustained suppression of gastric acid secretion. 8 Fexuprazan primarily undergoes hepatic metabolism, leading to the formation of metabolites M14, M11b, and M6. 9 However, these metabolites are considered pharmacologically inactive against the gastric H+/K+‐ATPase. 9 In vitro studies indicate that fexuprazan is metabolized by multiple cytochrome‐P450 enzymes (CYPs), including CYP3A4, CYP2B6, CYP2D6, and CYP2C19. 9 Among these enzymes, CYP3A4 plays a primary role in the formation of M14, which is a major metabolite of fexuprazan that is systemically present in a substantial proportion (68.3%). 9 Additionally, both fexuprazan and M14 demonstrated low potential for inhibiting or inducing CYP enzymes. In vitro microsomal studies reveal that inhibitory potential of both fexuprazan and M14 exhibit IC50 values greater than 10 μM for CYP enzymes, including CYP3A4, CYP1A2, CYP2D6, and CYP2C19. 9 Also, in vitro study suggests that induction potential of fexuprazan and M14 as an inducer of CYPs is low. 9 Furthermore, fexuprazan is not a substrate for uptake or efflux transporters. Fexuprazan and M14 have low potential for inhibitory effects on transporters at the effective dose of 40 mg (Appendix S1). 9
NSAIDs are commonly used in clinical practice for their anti‐inflammatory and analgesic properties. These drugs belong to various chemical classes, including propionic acid and acetic acid derivatives. In order to assess PK interactions between fexuprazan and NSAIDs, three different NSAIDs were chosen to represent each major class of drugs. 10 Celecoxib, naproxen, and meloxicam were selected as representative drugs of COX‐2 (cyclooxygenase‐2) selective inhibitors, propionic acid derivatives, and oxicam derivatives, respectively. Also, the frequency of prescription and high‐risk factor of NSAID‐induced peptic ulcers were taken into consideration. 11 , 12
Celecoxib is primarily metabolized by CYP2C9, with a minor portion of metabolism occurring via CYP3A4, and has moderate inhibitory effects on CYP2D6. 13 , 14 Naproxen is oxidized by CYP2C9 and CYP1A2, and is not considered to be a significant inhibitor of CYP enzymes. 13 , 15 Meloxicam is mostly hydroxylated by CYP2C9 and partially by CYP3A4, and is a relatively weak inhibitor of CYP2C9. 13 , 16 The elimination half‐lives of celecoxib, naproxen, and meloxicam are 12.4 h, 14 12–17 h, 15 and 19.6 h, 16 respectively.
In the context of acidic environments, the absorption of acidic NSAIDs like ibuprofen can be enhanced, but the effect of gastric acid suppression agents appears to be minimal. Previous studies indicate no significant PK interaction between NSAIDs and proton pump inhibitors (PPIs) suggesting PKs of NSAIDs are unaffected by gastric pH. 17 , 18
Although the combination therapy of fexuprazan and NSAIDs is anticipated to prevent NSAID‐induced peptic ulcers, the potential drug–drug interactions between fexuprazan and NSAIDs when co‐administered have not been assessed. Despite in vitro data suggest a low potential of drug–drug interaction, the assessment of interactions is necessary to ensure safety and optimize therapeutic efficacy in clinical practice. Therefore, this study aimed to evaluate the PK interactions between fexuprazan and NSAIDs in healthy subjects.
METHODS
Study introduction
This study was approved by the Institutional Review Board (IRB) at Seoul National University Hospital, Seoul National University Bundang Hospital, and Jeonbuk National University Hospital. The IRB at each individual site reviewed and approved the study protocol and consent forms. The study was conducted in accordance with the Declaration of Helsinki and Korean Good Clinical Practice (KGCP) (ClinicalTrials.gov registration number: NCT04490434). Healthy Korean male subjects between 19 and 50 years old with a body mass index (BMI) ranging from 18 to 27 kg/m2 were enrolled in the study, and written informed consent was obtained from each subject prior to any study‐related procedures.
Study design and procedures
A randomized, open‐label, multicenter, six‐sequence, one‐way crossover study was conducted. The study consisted of three cohorts categorized by treatments. The PK interactions between fexuprazan and celecoxib (Cohort 1), naproxen (Cohort 2), and meloxicam (Cohort 3) were evaluated at Seoul National University Hospital, Seoul, Republic of Korea, Seoul National University Bundang Hospital, Seongnam, Republic of Korea, Jeonbuk National University Hospital, Jeonju, Republic of Korea, respectively.
Fexuprazan and Celecoxib (Cohort 1)
In Arm A, subjects received twice‐daily oral doses of celecoxib 200 mg (Celebrex capsule 200 mg, Pfizer Korea) alone for 5 days, followed by consecutive co‐administration with fexuprazan 40 mg (Fexuclue tablet 40 mg, Daewoong Pharmaceutics, Ltd.) twice‐daily oral doses for 5 days and fexuprazan additionally administered for 1 day. In Arm B, fexuprazan 40 mg twice‐daily oral doses were administered alone for 5 days, followed by consecutive co‐administration with celecoxib 200 mg twice‐daily oral doses for 5 days and celecoxib additionally administered for 1 day (Figure 1 Cohort 1). To ensure consistent exposure of the perpetrator while the substrate was gradually removed, it was administered for an additional 1–2 days after discontinuing substrate dosing. Considering half‐lives of the drugs to achieve steady state, the number of doses and duration for each medication was determined.
FIGURE 1.
Study design. PSV, post‐study visit.
Fexuprazan and Naproxen (Cohort 2)
In Arm C, subjects received twice‐daily oral doses of naproxen 500 mg (Naxen‐F tablet 500 mg, Chong Kun Dang Pharmaceutical) alone for 5 days, followed by consecutive co‐administration with fexuprazan 40 mg twice‐daily oral doses for 5 days and fexuprazan additionally administered for 1 day. In Arm D, fexuprazan 40 mg twice‐daily oral doses were administered alone for 5 days, followed by consecutive co‐administration with naproxen 500 mg twice‐daily oral doses for 5 days and naproxen additionally administered for 1 day (Figure 1 Cohort 2).
Fexuprazan and Meloxicam (Cohort 3)
In Arm E, subjects received once‐daily oral doses of meloxicam 15 mg (Mobic capsule 15 mg, Boehringer‐ingelheim Korea Ltd.) alone for 7 days. Subsequently, they received consecutive co‐administration of fexuprazan 40 mg twice daily and meloxicam 15 mg once‐daily oral doses for 7 days and fexuprazan additionally administered for 2 days. In Arm F, fexuprazan 40 mg twice‐daily oral doses were administered alone for 5 days during the first period. This was followed by consecutive co‐administration of meloxicam 15 mg once daily and fexuprazan 40 mg twice‐daily oral doses for 7 days and meloxicam additionally administered for 1 day (Figure 1 Cohort 3).
PK blood samples were obtained for celecoxib, naproxen, fexuprazan and M14 at 0 (pre‐dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, and 48 h after dosing except for meloxicam at 0 (pre‐dose), 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 h after dosing. Around 8 mL of blood was collected in heparinized tubes for each sampling point. The plasma was obtained by centrifugation at 1800 g for 10 min at 4°C and stored at a temperature below −60°C until analysis.
Plasma concentrations of fexuprazan and M14 were determined by a liquid chromatography with tandem mass spectrometry (LC–MS/MS) using an AB SCIEX API 5000 mass spectrometer (Applied Biosystems/MDS Sciex, Foster City, CA, USA). The lower limit of quantification (LLOQ) of fexuprazan and M14 were 0.2 μg/L and 0.6 μg/L, respectively. Plasma concentrations of celecoxib, naproxen, and meloxicam were obtained by LC–MS/MS using an AB SCIEX API 4000 mass spectrometer. The LLOQ of celecoxib, naproxen, and meloxicam was 5 μg/L, 0.5 μg/L, and 10 μg/L, respectively (Appendix S1).
Pharmacokinetic assessments
PK assessments were conducted on subjects who completed the study with quantifiable concentrations of study drugs. PK parameters were estimated by non‐compartmental methods using Phoenix WinNonlin® (Certara, NJ, USA). The primary PK parameters were maximum plasma concentration at steady state (C max,ss) and area under the plasma concentration–time curve over the dosing interval of substrate (Arm A, B, C, D, F: 12 h, Arm E: 24 h) at steady state (AUCτ,ss) calculated by the linear‐up/log‐down trapezoidal method. The secondary PK parameters at steady state were time to reach C max,ss (T max,ss), terminal elimination half‐life (t 1/2,ss), clearance (CLss/F), and volume of distribution (V ss/F). Metabolic ratio is determined by AUCτ,M14/AUCτ,fexuprazan only for fexuprazan.
Safety and tolerability assessments
Safety and tolerability assessments were evaluated in all subjects who received at least one dose of study the drug throughout the entire study period. The assessment included monitoring of adverse events (AEs), vital signs, physical examinations, 12‐lead electrocardiograms (12‐lead ECGs), and clinical laboratory tests.
Sample size and statistical analysis
The sample size of each treatment arm was determined based on the intra‐subject variability for PK parameters of the substrate. Previous studies indicated that the intra‐subject variability for C max and AUClast of fexuprazan was at most 19.4%. In addition, previously reported intra‐subject variability for the PK parameter (C max) of NSAIDs is 31.8% (celecoxib), 8.4% (naproxen), and 9.8% (meloxicam), respectively. Assuming no difference in the PK characteristics of the combination compared with the monotherapy within each arm, the number of subjects required to detect PK interaction at a 0.05 significance level with 80% power was established by each arm. (Arm A: 38 subjects, Arm C, E: 12 subjects, and Arm B, D, F: 16 subjects).
SAS® (Version 9.4, SAS Institute Inc., NC, USA) was used for statistical analysis. Log‐transformed C max,ss and AUCτ,ss of fexuprazan, M14, celecoxib, naproxen, and meloxicam were calculated, and normality was tested. Analyses of variance (ANOVA) model was used to compare PK between treatments. The treatment was included as a fixed effect, and the inter‐individual difference was considered as a random effect in the model. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the combination therapy to monotherapy were estimated in each treatment arm. The equivalence range of 0.80–1.25 was considered as a no‐effect boundary, where 90% CIs entirely fell within this range. 16 Based on this criterion, the statistical significance of PK interactions was evaluated between treatments.
RESULTS
Study population
A total of 111 healthy subjects were randomized in each treatment arm and 103 subjects completed the study; Cohort 1: 49 subjects (Arm A: 34 subjects & Arm B: 15 subjects), Cohort 2: 26 subjects (Arm C: 11 subjects & Arm D: 15 subjects), and Cohort 3: 28 subjects (Arm E: 12 subjects & Arm F: 16 subjects).
The mean (±standard deviation) values of age, weight, height, and body mass index (BMI) of 111 subjects who randomized were 28.3 ± 7.1 years, 70.6 ± 8.3 kg, 174.6 ± 5.3 cm, and 23.1 ± 2.3 kg/m2, respectively. The demographic characteristics were comparable between two arms in each cohort (Table S1).
Pharmacokinetic interactions
Fexuprazan and Celecoxib (Cohort 1)
The systemic exposure of celecoxib was slightly higher when co‐administered with fexuprazan, but the GMRs and 90% CIs of C max,ss and AUCτ,ss for combination therapy to celecoxib monotherapy were within the equivalence range of 0.8–1.25 (Table 1, Figure 3).
TABLE 1.
Comparison of pharmacokinetic parameters of fexuprazan and three different kinds of NSAIDs at steady state.
| Parameters | Combination therapy | Monotherapy | GMR a (90% CI) | |
|---|---|---|---|---|
| Cohort 1 | ||||
| Celecoxib | C max,ss (μg/L) | 1200.3 ± 392.7 | 1079.9 ± 314.7 | 1.10 (1.01–1.20) |
| AUCτ,ss (h∙μg/L) | 8106.4 ± 2548.7 | 6940.9 ± 2126.8 | 1.16 (1.09–1.23) | |
| T max,ss (h) | 3.0 [1.0–6.0] | 2.5 [1.0–6.0] | ||
| t 1/2 (h) | 9.5 ± 3.3 | 9.4 ± 5.0 | ||
| CLss/F (L/h) | 26.9 ± 7.9 | 31.0 ± 7.8 | ||
| V ss/F (L) | 358.5 ± 125.6 | 415.7 ± 234.8 | ||
| Fexuprazan | C max,ss (μg/L) | 71.3 ± 32.4 | 65.6 ± 30.1 | 1.10 (0.98–1.23) |
| AUCτ,ss (h∙μg/L) | 570.2 ± 255.7 | 555.3 ± 239.6 | 1.03 (0.95–1.12) | |
| T max,ss (h) | 2.5 [1.0–6.0] | 3.0 [1.0–6.0] | ||
| t 1/2 (h) | 8.5 ± 0.8 | 8.7 ± 1.2 | ||
| CLss/F (L/h) | 92.0 ± 58.5 | 96.2 ± 65.5 | ||
| V ss/F (L) | 1136.7 ± 730.7 | 1203.2 ± 788.6 | ||
| M14 | C max,ss (μg/L) | 227.5 ± 56.3 | 213.9 ± 69.1 | 1.09 (1.01–1.17) |
| AUCτ,ss (h∙μg/L) | 1651.6 ± 486.8 | 1528.0 ± 503.4 | 1.09 (1.03–1.16) | |
| MR b | 3.82 ± 2.72 | 3.56 ± 2.50 | ||
| Cohort 2 | ||||
| Naproxen | C max,ss (mg/L) | 114.1 ± 12.9 | 104.3 ± 10.8 | 1.09 (1.05–1.14) |
| AUCτ,ss (h∙mg/L) | 907.4 ± 110.9 | 868.8 ± 112.9 | 1.05 (1.02–1.07) | |
| T max,ss (h) | 1.5 [0.5–3.0] | 3.0 [1.0–4.0] | ||
| t 1/2 (h) | 20.7 ± 2.3 | 19.3 ± 2.0 | ||
| CLss/F (L/h) | 558.4 ± 66.9 | 584.5 ± 76.4 | ||
| V ss/F (L) | 16612.6 ± 2648.7 | 16174.5 ± 2143.0 | ||
| Fexuprazan | C max,ss (μg/L) | 89.2 ± 52.5 | 72.5 ± 37.0 | 1.22 (1.02–1.46) |
| AUCτ,ss (h∙μg/L) | 728.7 ± 463.2 | 591.7 ± 271.7 | 1.19 (1.00–1.43) | |
| T max,ss (h) | 3.0 [1.5–4.0] | 2.5 [1.0–6.0] | ||
| t 1/2 (h) | 7.8 ± 1.1 | 8.6 ± 0.9 | ||
| CLss/F (L/h) | 69.5 ± 33.7 | 82.2 ± 37.9 | ||
| V ss/F (L) | 808.9 ± 503.9 | 1028.6 ± 506.2 | ||
| M14 | C max,ss (μg/L) | 160.3 ± 35.1 | 186.6 ± 33.2 | 0.85 (0.78–0.94) |
| AUCτ,ss (h∙μg/L) | 1149.4 ± 156.6 | 1321.5 ± 231.5 | 0.88 (0.83–0.92) | |
| MR | 2.03 ± 1.25 | 2.65 ± 1.22 | ||
| Cohort 3 | ||||
| Meloxicam | C max,ss (μg/L) | 2962.5 ± 750.1 | 2656.7 ± 528.6 | 1.10 (1.02–1.19) |
| AUCτ,ss (h∙μg/L) | 52597.2 ± 16378.9 | 45366.8 ± 12449.9 | 1.15 (1.08–1.22) | |
| T max,ss (h) | 4.5 [3.0–5.0] | 5.0 [4.0–6.0] | ||
| t 1/2 (h) | 28.6 ± 12.0 | 26.9 ± 11.0 | ||
| CLss/F (L/h) | 0.3 ± 0.1 | 0.4 ± 0.1 | ||
| V ss/F (L) | 11.8 ± 2.4 | 12.8 ± 3.3 | ||
| Fexuprazan | C max,ss (μg/L) | 83.2 ± 46.2 | 82.8 ± 45.5 | 0.94 (0.82–1.09) |
| AUCτ,ss (h∙μg/L) | 674.7 ± 379.2 | 728.3 ± 403.5 | 0.88 (0.79–0.98) | |
| T max (h) | 2.5 [1.5–4.0] | 2.5 [1.5–8.0] | ||
| t 1/2 (h) | 8.6 ± 2.1 | 9.6 ± 2.2 | ||
| CLss/F (L/h) | 97.9 ± 95.3 | 77.1 ± 54.8 | ||
| V ss/F (L) | 1427.7 ± 1984.4 | 1161.1 ± 1231.1 | ||
| M14 | C max,ss (μg/L) | 201.1 ± 38.1 | 179.9 ± 49.0 | 1.14 (1.06–1.22) |
| AUCτ,ss (h∙μg/L) | 1489.9 ± 317.7 | 1386.1 ± 426.3 | 1.10 (1.04–1.16) | |
| MR | 3.36 ± 2.76 | 2.50 ± 1.64 | ||
Note: Data are presented as mean ± standard deviation, except for T max,ss, which is presented as median [minimum–maximum].
Abbreviations: C max,ss, maximum plasma concentration at steady state; AUCτ,ss, area under the concentration–time curve over the dosing interval at steady state; T max,ss, time to reach C max,ss; CLss/F, apparent clearance at steady state; V ss/F, apparent volume of distribution at steady state.
Geometric mean ratio and 90% confidence interval of combination to monotherapy.
Metabolic ratio of fexuprazan (AUCτ,M14/AUCτ,fexuprazan).
FIGURE 3.
Pharmacokinetic (PK) interactions between fexuprazan and NSAIDs. (a) Effects of fexuprazan on the PKs of NSAIDs, (b) Effects of NSAIDs on the PKs of fexuprazan.
For fexuprazan, mean plasma concentration–time profiles were comparable between combination and monotherapy, and the corresponding values of combination therapy to fexuprazan monotherapy were also within the range of 0.8–1.25 (Table 1, Figure 3). The mean (±standard deviation) values of metabolic ratio for combination therapy and monotherapy were 3.82 ± 2.72 and 3.56 ± 2.50, respectively.
Fexuprazan and Naproxen (Cohort 2)
Mean plasma concentration–time profiles of naproxen were comparable between combination with fexuprazan and naproxen monotherapy (Figure 2). The GMRs and 90% CIs of C max,ss and AUCτ,ss for combination therapy to naproxen monotherapy were within the range of 0.8–1.25 (Table 1, Figure 3).
FIGURE 2.
Mean plasma concentration–time profiles of fexuprazan and NSAIDs at steady state after multiple administrations with a linear scale. Error bars represent standard deviation.; (a) celecoxib (Cohort 1), (b) fexuprazan (Cohort 1), (c) naproxen (Cohort 2), (d) fexuprazan (Cohort 2), (e) meloxicam (Cohort 3), and (f) fexuprazan (Cohort 3).
The systemic exposure of fexuprazan was increased when co‐administered with naproxen compared with fexuprazan alone. The GMRs (90% CIs) of C max,ss and AUCτ,ss for combination therapy with naproxen to fexuprazan monotherapy were 1.22 (1.02–1.46) and 1.19 (1.00–1.43), respectively. Although the 90% CIs were not entirely within the range of 0.8–1.25, the extent of the interaction was not deemed significant. These changes were judged not clinically meaningful. The mean (±standard deviation) values of metabolic ratio for combination therapy and monotherapy were 2.03 ± 1.25 and 2.65 ± 1.22, respectively.
Fexuprazan and Meloxicam (Cohort 3)
The systemic exposure of meloxicam was slightly higher when co‐administered with fexuprazan, but the GMRs and 90% CIs of C max,ss and AUCτ,ss for combination therapy to meloxicam monotherapy were within the range of 0.8–1.25 (Table 1, Figure 3).
For fexuprazan, mean plasma concentration–time profiles were comparable between combination and monotherapy. The GMRs (90% CIs) of C max,ss and AUCτ,ss for combination therapy with meloxicam to fexuprazan monotherapy were 0.94 (0.82–1.09) and 0.88 (0.79–0.98), respectively (Table 1, Figure 3). The 90% CI of AUCτ,ss was slightly decreased in the range of 0.8–1.25, but the ratio was still within an acceptable range. The mean (±standard deviation) values of metabolic ratio for combination therapy and monotherapy were 3.36 ± 2.76 and 2.50 ± 1.64, respectively.
Safety and tolerability
In Cohort 1, 10 AEs were observed in five subjects (33.3%) after fexuprazan administered alone and seven AEs were observed in six subjects (40.0%) after combination therapy with celecoxib (Table S2). Only one subject who experienced rash during the celecoxib monotherapy was discontinued the study drug. This subject received celecoxib 200 mg twice daily for 5 days, and a mild rash began on Day 4. Co‐administration of celecoxib 200 mg and fexuprazan 40 mg was started on Day 7, but due to this AE, administration was discontinued after Day 8. The observed rash is suspected to be a drug‐induced hypersensitivity reaction associated with the use of NSAIDs. The subject was treated for the AE and recovered without any sequelae.
In Cohort 2, six AEs were observed in five subjects (33.3%) after fexuprazan administered alone and 12 AEs were observed in seven subjects (46.7%) after the combination therapy with naproxen. In Cohort 3, eight AEs were observed in four subjects (23.5%) after fexuprazan administered alone, and 11 AEs were observed in five subjects (31.3%) after the combination therapy with meloxicam (Table S2). All AEs were mild, and all subjects were recovered without sequelae. There were no clinically significant changes observed in vital signs, physical examinations, clinical laboratory tests and 12‐lead ECGs in all cohorts.
DISCUSSION
In the present study, we aimed to assess the PK interactions between fexuprazan and three different kinds of NSAIDs. The combination therapy of fexuprazan with NSAIDs did not significantly alter the PK parameters of the NSAIDs when compared to the monotherapy with NSAIDs alone. This can be attributed to the fact that each NSAID is predominantly metabolized by CYP2C9 enzyme, while fexuprazan does not exhibit inhibitory or inducible effects on CYP2C9. Consequently, fexuprazan did not exert a notable effect on the PKs of NSAIDs.
However, the effects of NSAIDs on the PKs of fexuprazan varied among the different NSAIDs. Co‐administration of fexuprazan with celecoxib and meloxicam did not lead to significant changes in the PK parameters of fexuprazan, as compared to the fexuprazan monotherapy. In contrast, when naproxen was co‐administered with fexuprazan, there was a mild increase of approximately 20% in the systemic exposure of fexuprazan. Both the C max,ss and AUCτ,ss of fexuprazan increased by less than 25%, which is a generally accepted criterion for defining a weak inhibitor in drug interaction studies. 19 , 20 Notably, fexuprazan undergoes metabolism primarily via the CYP3A4 enzyme, which is mainly responsible for the formation of its metabolite M14. The decrease in metabolic ratio suggests that naproxen competitively inhibits the metabolism of fexuprazan into M14. Further investigations into the metabolism of fexuprazan are needed to comprehensively evaluate the PK interactions between fexuprazan and naproxen.
The previous phase I study reported exposure–response relationship and safety profile of fexuprazan. 8 Fexuprazan has a clear exposure–response relationship between AUCτ,ss and the percentage of time with intragastric pH ≥4 over 24 h, which is a primary pharmacodynamic parameter, and it is explained by a sigmoid E max model. 8 According to this model, we expect that the AUCτ,ss of fexuprazan 40 mg multiple dose twice daily resulted from the present study, reach 60%–80% of the time with intragastric pH ≥4 over 24 h, regardless of whether it is co‐administered with NSAIDs or not. Our study shows that the acid‐inhibitory effect of fexuprazan is not significantly impacted by the altered exposure during combination therapy with NSAIDs compared with monotherapy. Previous studies have established the safety and tolerability of fexuprazan at multiple doses of up to 160 mg for 7 days, with a single dose up to 320 mg. 8 Therefore, the slight increase in systemic exposure of fexuprazan by naproxen was determined to be within a safe range.
There is a limitation that only healthy males were evaluated in this study. Healthy males or females were eligible to participate in this study, but all subjects who were enrolled in all study parts were male. But it is noteworthy that no gender‐based dose adjustment required as per fexuprazan label recommended.
The safety and tolerability of fexuprazan were demonstrated when administered alone. When co‐administered with celecoxib, naproxen, and meloxicam, the combination therapy was well‐tolerated by all study subjects, with only one subject discontinuing due to a rash, which was likely caused by multiple administrations of celecoxib leading to drug‐induced hypersensitivity. The safety results suggest that the combinations of fexuprazan with these NSAIDs are generally well‐tolerated and do not raise substantial safety concerns.
Overall, the systemic exposure of fexuprazan and NSAIDs did not significantly change after the co‐administration. Even though fexuprazan exposure increased in combination therapy with naproxen, the extent of interactions was within the therapeutic range. These results may support the co‐administration of fexuprazan and NSAIDs for the prevention of NSAID‐induced peptic ulcer. Consequently, there appears to be no need for dose adjustment when fexuprazan is co‐administered with any of the commonly administered NSAIDs.
AUTHOR CONTRIBUTIONS
E.K., S.H.L., J.Y.C, M.G.K., and I.J.J. designed the research. E.K., S.H.L., J.Y.C., M.G.K., and I.J.J. performed the research. H.W., S.H.L., J.Y.C, M.G.K., and I.J.J. analyzed the data. H.W. and S.H.L. drafted the manuscript. All authors have reviewed, revised, and approved the final version of the manuscript.
FUNDING INFORMATION
This study was sponsored by Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea.
CONFLICT OF INTEREST STATEMENT
Jihye Chae and Hyejung Lee are current employees of Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea. All other authors declared no competing interests for this work.
Supporting information
Appendix S1.
ACKNOWLEDGMENTS
Heejae Won received a scholarship from the BK21 FOUR educational program. The author's affiliations are listed as of the time this study was conducted.
Won H, Kim E, Chae J, et al. Pharmacokinetic interactions between fexuprazan, a potassium‐competitive acid blocker, and nonsteroidal anti‐inflammatory drugs in healthy males. Clin Transl Sci. 2024;17:e13798. doi: 10.1111/cts.13798
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to confidentiality restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1.
Data Availability Statement
The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to confidentiality restrictions.