Research ArticleClinical Studies
Open Access

Disproportionality Analysis of Hepatotoxic and Gastrointestinal Adverse Events Associated With Nintedanib Using the Japanese Adverse Drug Event Report (JADER) Database

MASAKI FUJIWARA, HIROAKI IKESUE, KENTA YAMAOKA, MAYAKO UCHIDA, YOSHIHIRO UESAWA, NOBUYUKI MUROI and TADASHI SHIMIZU
In Vivo January 2025, 39 (1) 396-403; DOI: https://doi.org/10.21873/invivo.13841

Abstract

Background/Aim: Nintedanib may cause adverse events such as elevated liver enzyme levels, diarrhea, and decreased appetite. These adverse events should be managed appropriately as they affect the quality of life of patients. This study has aimed to analyze patient characteristics and time-to-onset of adverse events caused by nintedanib using the Japanese Adverse Drug Event Report (JADER) database. Patients and Methods: Data from April 2004 to June 2023 were extracted from the JADER database and the patient characteristics of nintedanib administration were evaluated using reported odds ratio (ROR) and 95% confidence interval (95%CI). The data were analyzed for time-to-onset and patient characteristics such as age, sex, body mass index (BMI), and the presence or absence of prednisolone. Results: The JADER database included 1,419 adverse event reports in which nintedanib was suspected. The number (%) and ROR of adverse events known to occur with the use of nintedanib were 72 (5.07%) cases of decreased appetite [ROR=7.09 (95%CI=5.59-8.99)], and 79 (5.57%) cases of diarrhea [ROR=6.52 (5.19-8.18)]. The median days until onset were 19.5 (IQR=6.25-50.5) days for hepatotoxicity, 119.5 (IQR=24.5-258.5) days for diarrhea, and 131.5 (IQR=20.5-334.5) days for decreased appetite. Conclusion: Nintedanib is more likely to cause elevated liver enzyme levels, diarrhea, and decreased appetite than other drugs. These events occurred within approximately 3-4 months. The concomitant use of prednisolone may also be associated with gastrointestinal hemorrhage.

Key Words:

Nintedanib is a tyrosine kinase inhibitor that targets platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR) (1). These receptors have been reported to be involved in idiopathic pulmonary fibrosis (IPF) (2), systemic sclerosis-associated interstitial lung disease (SSc-ILD) (3), and progressive fibrosing interstitial lung disease (PF-ILD) (4). Nintedanib significantly reduces the decline in respiratory function [annual rate of decrease in forced vital capacity (FVC)] when compared with placebo in patients with IPF, SSc-ILD, and PF-ILD (2-4). Therefore, nintedanib is used to treat diseases associated with decreased respiratory function (2-4).

Although nintedanib has an effective therapeutic effect, there have been several reports of adverse events caused by nintedanib exposure. In an international phase III clinical trial, elevated hepatic enzyme levels and gastrointestinal adverse events were observed in some patients treated with nintedanib (5). Additionally, hepatic and gastrointestinal adverse events have been identified in phase III studies in Japanese patients (5-7). In a post-marketing survey in Japan, the most common adverse events affecting discontinuation within 12 months of administration were liver function abnormalities and diarrhea (8). Furthermore, the incidence of gastrointestinal-related adverse events has been reported to increase in patients with a lower BMI (9, 10). Discontinuation of drug therapy due to hepatic and gastrointestinal adverse events may lead to a poor prognosis in IPF. However, information regarding the association between nintedanib exposure and hepatic and gastrointestinal adverse events in Japanese patients is still insufficient.

Assessing trends in the occurrence of hepatic and gastrointestinal adverse events after nintedanib treatment using an adverse event spontaneous reporting database may be a useful method to generate hypotheses about the possible relationship between adverse events and drugs. An analysis using the U.S. spontaneous reporting database suggested that the reported odds of liver toxicity may be higher in the nintedanib group than that seen in the pirfenidone group (11). Furthermore, studies using both Japanese and U.S. spontaneous reporting databases have shown that nintedanib may be involved in the development of drug-induced interstitial lung disease (12). Therefore, a detailed analysis of the association between nintedanib and hepatic and gastrointestinal adverse events in Japanese patients, using an adverse event database, would be clinically significant.

This study investigated the disproportionality, timing of occurrence, and patient characteristics of patient stratification trends of nintedanib-associated hepatic and gastrointestinal adverse events using the Japanese Adverse Event Report (JADER) database.

Patients and Methods

Data source. The JADER database comprises four datasets: patient statistics (DEMO), drug information (DRUG), adverse events (REAC), and medical history (HIST). The AEs were coded using the Japanese version of the ICH International Glossary of Drug Terminology (MedDRA/J) ver. 26.0, and ‘Preferred Term (PT)’ was used to represent terms in the REAC table. The data were collected between April 2004 and June 2023. The master data table for the analysis was prepared as follows: Duplicate cases were excluded from the DRUG and REAC tables. The corresponding case data from the DRUG, REAC, and DEMO tables were combined using identification numbers for each adverse event. The drugs were classified as “suspected drugs”, “concomitant drugs”, or “interactions” as the cause of adverse events.

Target adverse events definitions. In this study, hepatotoxicity was defined using standardized MedDRA query (SMQ) reports for hepatic function abnormal (code: 10019670), increased hepatic enzymes (code: 10060795), liver disorder (code: 10024670), and drug-induced liver injury (code: 10072268). Upper gastrointestinal disorder was defined as SMQ reports of nausea (code: 10028813) or vomiting (code: 10047700). Gastrointestinal hemorrhage (code: 10017955), diarrhea (code: 10012735), and decreased appetite (code: 10061428) were reported only in the applicable SMQ.

Calculation of reported odds ratio (ROR) and 95% confidence intervals (95%CI). Only the cases classified as “suspected drugs” were used in the analysis. RORs and 95%CIs were calculated for the disproportionality analysis of the target drugs associated with hepatic and gastrointestinal adverse events. The ROR and 95%CI were calculated using a 2×2 contingency table consisting of four categories: (a) number of patients with hepatic or gastrointestinal adverse events after taking targeted drugs, (b) number of patients with non-hepatic or gastrointestinal adverse events after taking targeted drugs, (c) number of patients with hepatic or gastrointestinal adverse events after taking non-targeted drugs, and (d) number of patients with non-hepatic or gastrointestinal adverse events after taking non-targeted drugs.

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Disproportionality was defined as being present when the lower limit of the 95% confidence interval (95%CI) of the ROR was >1 for adverse events with 10 or more reports (13).

Time-to-onset analysis. Time-to-onset was analyzed using data organized according to the date of dosing initiation and onset of adverse events. The number of days to onset was calculated by using the data obtained and adding 0.5 to the difference between the start date of administration and the date of onset of the first adverse event (14). If multiple adverse events occurred simultaneously in one patient, the total onset time was counted as one for that patient. In this study, the maximum time to the onset of adverse events was two years (730 days). Histograms were used in order to determine the number of days until the onset of adverse events. Weibull distribution was used to calculate the scale parameter α (63.4% cumulative days) and shape parameter β (15).

Subgroup analysis of age, sex, or BMI. The relationship between nintedanib and the patient characteristics of adverse events suspected to be associated with nintedanib was analyzed. Data including age, sex, height, and weight were used for the subgroup analysis. To ensure anonymity, the median values of height and weight were used, which are summarized in units of 10 cm and 10 kg, respectively. For example, data for “150 cm” range and “50 kg” range were set to “155 cm” and “55 kg”, respectively. For age stratification analysis, a master table was used to separate the over 70 years old group (N=781,808) from those under 70 years old (N=1,266,161). For sex analysis, a master table was used to separate the male (N=1,086,607) and female groups (N=1,043,132). The BMI was calculated from height and weight and divided into two groups: those above 22 (N=367,950) and those below 22 (N=425,155). In each group, the ROR and 95%CI were calculated, and disproportionality was considered present if the lower limit of the 95%CI was >1.

Subgroup analysis of concomitant use of prednisolone (PSL) group. Based on the “suspected drugs” and “concomitant drugs” in the master table, the groups were stratified according to concomitant use of prednisolone derivatives. The concomitant PSL group included reports of concomitant prednisolone, methylprednisolone sodium succinate, methylprednisolone, or prednisolone sodium succinate among the prednisolone products (N=296,234). The non-PSL concomitant group was defined by the absence of concomitant PSL (N=1,903,906). In each group, the ROR and 95%CI were calculated, and disproportionality was considered present if the lower limit of the 95%CI was >1.

Statistical analysis. Statistical analysis was performed using JMP Pro® 15.2 (SAS Institute, Cary, NC, USA).

Ethical approval. This study was conducted in compliance with the Ministry of Health, Labour and Welfare’s Ethical Guidelines for Epidemiological Studies. This study complied with the principles of the Declaration of Helsinki. This observational study used anonymized information from the JADER database and did not involve therapeutic intervention or the collection of human samples. Hence, this study was judged by the Ethical Review Committee of Hyogo Medical University to require no ethical approval.

Results

Disproportionality of the hepatotoxicity and gastrointestinal disorders with exposure of nintedanib. Of the 2,200,140 adverse event reports evaluated in the analysis undertaken, 1,419 adverse events were suspected to be associated with the use of nintedanib. Among these patients, 187 had hepatotoxicity (13.18%), 24 had upper gastrointestinal disorders (1.69%), 11 had gastrointestinal hemorrhage (0.78%), 79 had diarrhea (5.57%), and 72 had decreased appetite (5.07%). Disproportionality was identified in hepatotoxicity [ROR=4.57 (95%CI=3.91-5.33)], gastrointestinal hemorrhage [ROR=2.40 (95%CI=1.32-4.34)], diarrhea [ROR=6.52 (95%CI=5.19-8.18)] and decreased appetite [ROR=7.09 (95%CI=5.59-8.99)]. On the other hand, no disproportionality was detected in upper gastrointestinal disorder [ROR=1.45 (95%CI=0.97-2.18)] (Table I).

View this table:
Table I.

Number of reported adverse events and reported odds ratios (RORs) associated with nintedanib.

Time to onset analysis. The values for median interquartile range (IQR) of time to onset were 19.5 days (IQR=6.25-50.5) for hepatotoxicity, 27 days (IQR=2.25-75.2) for upper gastrointestinal disorder, 220.5 days (IQR=37-359.5) for gastrointestinal hemorrhage, 119.5 days (IQR=24.5-258.5) for diarrhea, and 131.5 days (IQR=20.5-334.5) for decreased appetite (Table II, Figure 1). The upper limit of 95%CI for the shape parameter β in the Weibull distribution of hepatotoxicity, upper gastrointestinal disorder, diarrhea, and decreased appetite was β<1, indicating an early onset type (Table II).

View this table:
Table II.

Time-to-onset analysis of nintedanib-associated adverse effects.

Figure 1.
Figure 1.

Histogram of nintedanib-associated adverse effects: 1) hepatotoxicity; 2) upper gastrointestinal disorder; 3) gastrointestinal hemorrhage; 4) diarrhea; and 5) decreased appetite.

ROR and 95%CI for sex, age, BMI, and the presence or absence of PSL group. We investigated the occurrence of adverse events according to age, sex, BMI, and the presence or absence of PSL. Hepatotoxicity and decreased appetite were disproportionately detected in the overall analysis, and disproportionality was also detected in all factors in the stratified analysis. Although no disproportionality was detected for upper gastrointestinal disorder in the overall analysis, disproportionalities were detected in ≥70 years [ROR=2.13 (1.38-3.29)] and BMI ≥22 [ROR=2.15 (95%CI=1.15-4.04)] in the stratified analysis (Table III). While disproportionality was detected in gastrointestinal hemorrhage in the overall analysis, disproportionalities were not detected in ≥70 years [ROR=1.40 (0.67-2.95)] and without PSL [ROR=1.46 (0.61-3.51)]. Disproportionality was detected in diarrhea in the overall analysis; no disproportionality was detected in male [ROR=1.13 (0.47-2.73)].

View this table:
Table III.

Analysis of sex, age, BMI and the presence or absence of prednisolone (PSL) on main adverse events in patients administered nintedanib.

Discussion

Statement of key findings. Disproportionality was detected in the occurrence of hepatotoxicity, gastrointestinal hemorrhage, diarrhea, and decreased appetite in patients treated with nintedanib. The median times to the onset of hepatotoxicity and upper gastrointestinal disorders were 19.5 and 27 days, respectively. In contrast, the medians of gastrointestinal hemorrhage, diarrhea, and decreased appetites were 119 days or more. Based on the stratified analysis, differences in disparity were identified in BMI and age in the stratified analysis of upper gastrointestinal disorders. There were disproportionate differences in gastrointestinal bleeding according to age and PSL use. In addition, a disproportionate sex difference was detected for diarrhea.

Strengths and weaknesses. This study had several limitations. First, the JADER database is a spontaneous reporting system and may be prone to reporting biases such as underreporting and also overreporting. This may explain why the results show increased frequencies for certain factors. Second, there was limited information on the post-administration details, including patient performance status, actual dose, and patient blood test data. In addition, no information was available on the severity of adverse events or the nutritional status of the patient. Therefore, an analysis considering the background factors, including disease severity, was difficult, and the influence of confounding factors could not be excluded. This finding suggests that the generalizability of our results is limited. Third, the age, height, and weight information used in the stratified analysis were reported in 10 years, 10 cm, and 10 kg increments, respectively. Therefore, the stratification was not completely accurate. However, this study showed a disproportionate patient population that may be predisposed to liver and gastrointestinal disorders among nintedanib recipients, which has rarely been reported to date.

Interpretation. Overall, disproportionality was observed in the occurrence of nintedanib-associated hepatotoxicity. Our findings were consistent with reports of hepatotoxicity in the INPULSIS trial and a Japanese single-center observational study (7, 16). The hepatotoxicity of nintedanib may be associated with hepatic metabolizing agents, as with other multikinase inhibitors (17). In our study, the median time to hepatotoxicity was 19.5 days, with the Weibull shape parameter indicating an early onset. In a single-center observational study of 32 Japanese subjects, the number of days until the occurrence of aspartate aminotransferase and alanine aminotransferase were 5.5 days (IQR=3.3-13.5) and 5.0 days (IQR=3.0-10.5), respectively (16). Although this study was based on spontaneous reports, the tendency for hepatotoxicity to occur early in the treatment process was similar to that observed in a single-center study. Disproportionality was detected in all strata in the stratified analysis performed in this study, suggesting that hepatotoxicity may occur regardless of sex, age, body mass index, or the presence or absence of PSL. In a Japanese single-center observational study, the incidence of elevated AST and/or ALT with CTCAE grade ≥2 was reported to be higher in the BMI <22 group than in the BMI ≥22 group (16). Meanwhile, the results of our disproportionality analysis by BMI stratum differed from those of a single-center study. The discrepancy between the study results may have been due to differences in the study design and the number of participants analyzed.

No disproportionality was observed in the overall population of patients with nintedanib-associated upper gastrointestinal disorders (nausea and vomiting). In contrast, disproportionality was detected in patients aged ≥70 years and those with a BMI <22. In clinical trials, nausea and vomiting did not differ in frequency between two groups stratified by age 75 years (9, 10, 18). The features of the JADER database, which is a 10-year age report and spontaneous report database, may have influenced the differences in our observations. A single-center study of 77 patients treated with nintedanib showed that BMI<21.6 was a risk factor for the development of nausea (9, 10). The results of this observational study differed from those of our disproportionality analysis. This may imply the need to accumulate sample sizes in observational studies in order to verify which BMI stratum is a risk factor. In our analysis, the median time to onset of the gastrointestinal disorder was 27 days (IQR=2.25-75.25), suggesting that it may be more likely to occur early in the course of treatment, as indicated by the beta parameter of the Weibull analysis. The median time to onset of nausea and vomiting after nintedanib administration was reported to be 6 and 44 days, respectively, with a minimum of 1 day (19). Our findings suggested a tendency toward early onset in Japanese patients.

Disproportionality was detected in the overall analysis of gastrointestinal bleeding associated with nintedanib administration. Our findings are consistent with reports suggesting that nintedanib may be involved in the development of upper gastrointestinal bleeding owing to its inhibitory effect on vascular endothelial growth factor receptors (20). In the stratified analyses, no disproportionality was detected between the two strata of age ≥70 years and no PSL. The effect of age is unknown. PSL has been shown to inhibit prostaglandin production and it is associated with the development of steroidal gastric ulcers (21). Thus, treatment with nintedanib and steroids may be associated with gastrointestinal bleeding through various mechanisms. In addition, our analysis showed that the number of days to onset was 220.5 (IQR=37-359.5). However, the number of reports on gastrointestinal hemorrhage suspected to be associated with nintedanib is small, thus further studies are required.

In our study, we detected disproportionality in the occurrence of diarrhea. Diarrhea is one of the most common adverse events associated with nintedanib use and should be monitored during clinical trials and post-marketing surveillance (2, 8). A subanalysis of the INPULSIS trial reported a median duration of diarrhea of 138.5 days in the nintedanib group (19), showing a trend similar to that of our calculated median of 119.5 days. Additionally, disproportionality was not detected in the male group in the stratified analysis. International clinical trials reported no differences in the incidence of diarrhea between male and female (22). Our study may have yielded different results owing to the differences in the study design and race. It has also been reported that the addition of prednisolone to nintedanib treatment reduces the incidence of diarrhea (9); however, this study showed an imbalance in both strata with and without prednisolone. The difference is unclear, but it suggests that follow-up is needed to determine whether concomitant use of PSL reduces the incidence of diarrhea in Japanese patients.

Our survey detected disproportionality in terms of decreased appetite. Decreased appetite was reported as an adverse event in the INPULSIS trial (7). In addition, a subanalysis of the INPULSIS trial reported that 10% of patients developed decreased appetite (19). Although the present study differs from the INPULSIS trial in terms of race and study design, the results suggest that nintedanib may reduce appetite. Disproportionality was also detected in the stratified analyses of sex, age, BMI, and presence/absence of PSL use; therefore, the existence of a predilection group could not be estimated. This difference in the trends may have been influenced by variations in the collected populations. In an observational study of Japanese patients receiving pirfenidone plus nintedanib, the mean time to onset of decreased appetite was 29-44 weeks (23). According to our disproportionality analysis, the time to disease onset was 131 days. Although the effects of pirfenidone cannot be ruled out, the results of the observational studies and our spontaneous reports suggest that monitoring for more than four months may be necessary.

Further research. Further studies are required in order to evaluate the association between nintedanib and hepatic and gastrointestinal disorders. As reporting bias exists in database studies using the JADER database, validity should be evaluated using medical information databases and other sources. In addition, observational studies at multiple centers are required to validate the timing of hepatic and gastrointestinal injuries in patients treated with nintedanib.

Conclusion

The results of this study suggest that nintedanib may be associated with increased liver enzyme levels, diarrhea, and decreased appetite. Our results can be used for the clinical monitoring of adverse drug reactions. In addition, the concomitant use of nintedanib and prednisolone may be associated with the development of gastrointestinal bleeding. This new aspect requires further analysis using more detailed patient information, such as medical record data.

Acknowledgements

The Authors would like to thank Editage (www.editage.com) for the English language editing.

Footnotes

  • Authors’ Contributions

    Mr. Fujiwara: Data curation, writing-original draft, review and editing, formal analysis. Dr. Ikesue: Conceptualization, writing-review and editing. Mr. Yamaoka: Data curation, writing-original draft. Dr. Uchida: Formal analysis, writing-original draft. Dr. Uesawa: Project administration, writing-original draft. Dr. Muroi: Funding acquisition, writing-original draft, supervision. Dr. Shimizu: Data curation, conceptualization, writing-original draft, writing-review and editing, supervision.

  • Funding

    The Authors have not disclosed any funding.

  • Conflicts of Interest

    All Authors declare no conflicts of interest in relation to this study.

  • Received September 7, 2024.
  • Revision received September 24, 2024.
  • Accepted September 25, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Disproportionality Analysis of Hepatotoxic and Gastrointestinal Adverse Events Associated With Nintedanib Using the Japanese Adverse Drug Event Report (JADER) Database
MASAKI FUJIWARA, HIROAKI IKESUE, KENTA YAMAOKA, MAYAKO UCHIDA, YOSHIHIRO UESAWA, NOBUYUKI MUROI, TADASHI SHIMIZU
In Vivo Jan 2025, 39 (1) 396-403; DOI: 10.21873/invivo.13841
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