Low body surface area predicts hepatotoxicity of nintedanib in patients with idiopathic pulmonary fibrosis

After the commercialization of nintedanib in Japan, a high incidence of hepatotoxicity resulting in treatment interruption was noted in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib in our hospital. This study aimed to clarify the risk factors for hepatotoxicity of nintedanib. Sixty-eight consecutive cases of IPF newly treated with nintedanib at a dose of 150 mg twice daily from September 2015 to September 2016 were enrolled: 46 patients (67.6%) exhibited aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevation and 16 patients (23.5%) also had a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2. Body surface area (BSA) was significantly lower in the CTCAE grade ≥2 group than in another group. A multivariate logistic regression analysis showed that the association between BSA and AST/ALT elevation with CTCAE grade ≥2 was statistically significant. Eight of 10 patients who resumed nintedanib at a reduced dose of 100 mg twice daily after interruption due to hepatotoxicity did not again develop AST/ALT elevation. In conclusion, a low BSA was associated with hepatotoxicity of nintedanib at a dose of 150 mg twice daily. It would be a good option for patients with a small physique to start nintedanib at a dose of 100 mg twice daily and then increase if possible after confirming its safety.

Risk factors for hepatotoxicity of nintedanib. We evaluated the risk factors for AST and/or ALT elevation with a CTCAE grade ≥2 (Table 4). Referring to the results of comparison with and without hepatotoxicity,   we selected BSA not only as the most possible candidate risk factor, but also as a representative factor related to physique. We also selected age, %FVC, %DLCO (these 3 factors had a significant impact on the assessment of severity and/or prognosis of IPF and have little relation with physique), and the baseline AST and ALT levels as candidate risk factors. A multivariate logistic regression analysis showed that the association between BSA and AST and/or ALT elevation with a CTCAE grade ≥2 was statistically significant (p = 0.0457). A ROC curve analysis was used to determine the BSA cut-off values (Fig. 1). The area under the curve for BSA was 0.664 (95% confidence interval: 0.515-0.813) and the cut-off value for which sensitivity + specificity is maximal was 1.58 m 2 (68.8% sensitivity and 65.4% specificity). Treatment after interruption due to hepatotoxicity. Treatments after interruption due to hepatotoxicity are summarized in Table 5. In 16 patients, treatment interruption was required due to AST and/or ALT elevation with a CTCAE grade ≥2. In all cases, hepatic enzyme elevations were completely reversible with treatment interruption. Among 16 patients who needed a treatment interruption due to AST and/or ALT elevation with a CTCAE grade ≥2, re-administration at a reduced dose of 100 mg twice daily was performed in 10 patients. Treatment was successfully continued in 6 patients, whereas it was stopped in 4 patients due to the recurrence of AST and/or ALT elevation with a CTCAE grade ≥2 (2 patients) and nausea or fever (1 patient each). On the other hands, the remaining 6 patients who needed a treatment interruption due to AST and/or ALT elevation with a CTCAE grade ≥2 discontinued nintedanib treatment without resumption because of patient rejection or acute hypochondriac pain (2 patients each) and a deterioration in their physical condition or eosinophilia (1 patient each).

Discussion
The present study demonstrated the 3 following important clinical observations. First, a low BSA was associated with AST and/or ALT elevation with a CTCAE grade ≥2 when treated with nintedanib at a dose of 150 mg twice daily. Second, 80% of the patients who resumed nintedanib at a reduced dose of 100 mg twice daily after treatment interruption due to hepatotoxicity did not again develop AST and/or ALT elevation with a CTCAE grade ≥2. Third, 37.5% of the patients who needed treatment interruption due to hepatotoxicity could not resume nintedanib treatment.
To date, risk factors for hepatotoxicity of nintedanib in patients with IPF have not been fully investigated. However, the present study suggested that a low BSA predicts an AST and/or ALT elevation with a CTCAE grade ≥2 when treating with nintedanib at a dose of 150 mg twice daily. The incidence of hepatotoxicity in the present study was considerably higher than that reported in the INPULSIS trials (as shown in Table 2), whereas factors related to physique such as body weight, BMI, and absolute FVC values were considerably lower than those reported in the INPULSIS trials (Table 1) 4 . Similarly, a sub-analysis of the INPULSIS trials revealed that the incidence of AST and/or ALT elevation was higher in Japanese populations than in overall populations (Table 2), whereas body weight, BMI, and absolute FVC values were lower in Japanese patients than those in the overall population (Table 1) 4,5,8,9 . Moreover, in a phase I study of nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer, the incidence of hepatotoxicity was higher in patients with a BSA < 1.50 m 2 than in patients with a BSA ≥1.50 m 2 10 . These results indicate that physique is related to hepatotoxicity of nintedanib. Among the factors related to physique, BSA would be the most useful predictive factor.  Table 2. Hepatotoxicity. Categorical data are presented as numbers (percentages). *The number of patients whose test results increased >the upper limit of the normal range/the number of patients whose test results were within the reference values at baseline. Abbreviations; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; T-Bil = total bilirubin; γ-GTP = γ-glutamyl transpeptidase; CTCAE = Common Terminology Criteria for Adverse Events.
It is also noteworthy that 8 of 10 patients (80%) successfully resumed nintedanib at a reduced dose of 100 mg twice daily after treatment interruption due to AST and/or ALT elevation with a CTCAE grade ≥2 at a dose of 150 mg twice daily. These 8 patients also had a small physique, with a median BSA of 1.57 m 2 . According to the pharmacokinetic analysis of nintedanib in Japanese patients, the area under the concentration-time curve and maximum concentration in plasma at a steady state were approximately two-times higher at a dose of 150 mg twice daily than those at a dose of 100 mg twice daily (39.7 ng/ml vs 20.0 ng/ml and 218 ng·h/ml vs 115 ng·h/ ml, respectively) 11 . These data suggested that hepatotoxicity would be associated with the plasma concentration of nintedanib. In the present study, it was speculated that the patients with a small build tended to have a high serum concentration at a dose of 150 mg twice daily, and thus, were more likely to develop AST and/or ALT elevation. However, as the bioavailability of nintedanib is relatively low, serum concentration of nintedanib may     Table 4. Multivariate logistic regression analysis.
differ among individuals. Therefore, further pharmacokinetic analysis in various patients with different physiques is required. In the present study, an AST and/or ALT elevation was completely reversible with a treatment interruption. However, 6 of the 16 patients (37.5%) who needed a treatment interruption due to AST and/or ALT elevation with a CTCAE grade ≥2 could not resume nintedanib treatment. It might have been unavoidable that those patients could not resume because of concerns over noteworthy side-effects such as eosinophilia in the peripheral blood and acute hypochondriac pain. However, at least another 3 patients were highly likely to have continued nintedanib treatment over a longer period if it were not for the interruption. In addition, recently, an interim analysis of the INPULSIS ® -ON study showed that the beneficial effect of nintedanib on slowing disease progression was maintained and the change from baseline FVC was consistent over 2 or more years 12 . Thus, it is very important to continue nintedanib treatment as long as possible without interruption and/or discontinuation by setting  the appropriate dosage for individual patients. For patients with a small physique, especially Japanese and eastern Asian patients with a BSA <1.58 m 2 , it would be a good option to start nintedanib at a dose of 100 mg twice daily and then increase the dose to 150 mg twice daily if possible after confirming its safety. A limitation of the present study was the retrospective single-center study design. In addition, frequent blood sampling may provide an opportunity to detect a temporal AST and/or ALT elevation that may recover spontaneously. In the present study, the median interval from nintedanib initiation to AST and/or ALT elevation with a CTCAE grade ≥2 was only 6 days, whereas the protocol of the INPULSIS trials specified that hepatic enzymes must be examined once every 2 weeks during the first 6 weeks. The short observation period was also another limitation when assessing long-term safety.
In conclusion, a low BSA was associated with hepatotoxicity of nintedanib at a dose of 150 mg twice daily in patients with IPF. To continue nintedanib treatment as long as possible without interruption and/or discontinuation, it would be a good option for patients with a small physique to start nintedanib at a dose of 100 mg twice daily and then increase the dose to 150 mg twice daily if possible after confirming its safety.

Patients and settings. This retrospective study was performed at the Kanagawa Cardiovascular and
Respiratory Center in Yokohama City, Kanagawa, Japan. All consecutive cases of IPF newly treated with nintedanib at a dose of 150 mg twice daily from September 2015 to September 2016 were enrolled. The diagnosis of IPF was based on the official American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association statement of 2011 13 . Patients with a previous history of nintedanib treatment (formerly known as BIBF1120) were excluded. This study has been carried out in accordance with the Declaration of Helsinki. The Ethics Committee of the Kanagawa Cardiovascular and Respiratory Center approved the study protocol (Approval date: November 30, 2016; Approved number: KCRC-16-0006) and patient consent was waived because this was a retrospective study and anonymity was secured.
Data availability. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Clinical and laboratory findings. Clinical and laboratory data used in this study were retrieved from patient medical records and included age, gender, height, body weight, laboratory data [AST, ALT, alkaline phosphatase (ALP), total bilirubin (T-Bil), γ-glutamyl transpeptidase (γ-GTP), serum creatinine, Krebs von den Lungen-6 (KL-6), and surfactant protein D (SP-D)], pulmonary function tests, six minute walk test, and concomitant therapy. In all cases, hepatic enzymes were examined at least once within a week of nintedanib treatment initiation and at least once every 2-4 weeks thereafter.