Negative Impact of Anorexia and Weight Loss During Prior Pirfenidone Administration on Subsequent Nintedanib Treatment in Patients With Idiopathic Pulmonary Fibrosis

Satoshi Ikeda; Akimasa Sekine; Tomohisa Baba; Takuma Katano; Erina Tabata; Ryota Shintani; Shinko Sadoyama; Hideaki Yamakawa; Tsuneyuki Oda; Ryo Okuda; Hideya Kitamura; Tae Iwasawa; Tamiko Takemura; Takashi Ogura


BMC Pulm Med. 2019;19(78) 

In This Article



Thirty IPF patients were enrolled in this study and patient characteristics observed just before initiating nintedanib are summarized in Table 1. Most of the included patients were males (76.5%) and the median age was 72 years old. The median body weight, body mass index (BMI), and body surface area (BSA) estimated using the Du Bois formula were 54.9 kg, 21.0, and 1.59 m2, respectively. The median percent predicted FVC (%FVC) and percent predicted diffusing capacity for lung carbon monoxide (%DLco) at baseline were 52.9 and 44.2%, respectively. The physique-related factors, absolute FVC values, and %FVC were considerably lower than those reported in the INPULSIS trials; as for the Japanese patients of nintedanib group in the INPULSIS trials, the mean body weight, BMI, absolute FVC value, and %FVC were 63.8 kg, 24.4, 2.42 L, and 80.9%, respectively. Twenty-seven patients (90%) revealed definite usual interstitial pneumonia pattern on high-resolution computed tomography, and 8 patients (26.7%) have undergone surgical lung biopsy for the diagnosis of IPF.

Twenty-three patients (76.6%) were switched to nintedanib with an interruption period of less than 1 month, and the median duration of prior pirfenidone treatment was 8.3 months. Fifteen patients (50%) were switched to nintedanib because of FVC decline and 15 patients (50%) because of intolerable AEs. The median follow-up duration from the initiation of nintedanib was 10.4 months (data cutoff date was October 4, 2017).

Adverse Events

The details of AEs during the pirfenidone and nintedanib administration periods are summarized in Table 2. The most common AE of nintedanib was AST/ALT elevation (63.3%), followed by anorexia (46.7%), diarrhea (46.7%), and weight loss (20.0%), whereas the most common CTCAE grade ≥ 2 AE was anorexia (36.7%), followed by diarrhea (26.7%) and AST/ALT elevation (23.3%). By contrast, during the pirfenidone administration period, 19 patients (63.3%) exhibited anorexia, and 16 patients (53.3%) had a CTCAE grade of ≥2. In addition, 17 patients (56.7%) exhibited weight loss with a CTCAE grade of ≥1 (≥5% from baseline), and seven patients (23.3%) had a CTCAE grade of ≥2 (≥10% from baseline).

Treatment Status of Nintedanib During the Observation Period

The treatment status during the observation period is summarized in Table 3. Eighteen patients (60.0%) discontinued nintedanib during the observation period. Notably, 16 patients (53.3%) discontinued nintedanib within 6 months. The most common causes of discontinuation were liver injury, anorexia along with weight loss, deterioration of physical condition, death, and acute exacerbation of IPF (10% each). Only 7 patients (23.3%) continued nintedanib without interruption and/or dose reduction.

Efficacy of Nintedanib in Patients Switched From Pirfenidone

Figure 1 shows the decline of FVC per month during the periods of pirfenidone administration [(FVC value just before nintedanib initiation – most recent FVC value during pirfenidone administration period)/examination interval] and the decline of FVC per month after switching to nintedanib [(FVC value at 6 months after nintedanib initiation - FVC value just before nintedanib initiation)/examination interval]. Only 10 patients could undergo lung function tests at 6 months after switching to nintedanib. However, in 7 of 10 patients (70%), nintedanib suppressed FVC decline compared with that observed during the pirfenidone administration period.

Risk Factors for the Early Termination of Nintedanib

As stated, 16 patients (53.3%) discontinued nintedanib within 6 months (early termination group), whereas 14 patients (46.7%) received nintedanib for ≥6 months (continuous treatment group). A comparison of the clinical and laboratory data between the two groups (Table 4) revealed that BMI and body weight were significantly lower in the early termination group than in the continuous treatment group (p = 0.007 and 0.048, respectively). Logistic regression analysis was performed to verify the risk factors for the early termination of nintedanib (Table 5). Univariate analysis identified a significant association between low BMI and early termination of nintedanib (p = 0.0239). We selected BMI not only as the most likely candidate risk factor but also as a representative factor related to physique. We also selected weight loss with a CTCAE grade of ≥2 occurring during the pirfenidone administration period and surfactant protein D (SP-D) (both P ≤ 0.1 in univariate analysis) as candidate risk factors. Multivariate logistic regression analysis using backward stepwise selection revealed a statistically significant association between BMI and the early termination of nintedanib (p = 0.0111).

Comparison Between the Switch and Pirfenidone-naïve Groups

A comparison of the baseline characteristics (observed just before nintedanib initiation) and data related to nintedanib therapy between the aforementioned study participants (switch-group, N = 30) and other IPF patients who were newly started on nintedanib without any prior anti-fibrotic treatment at our hospital (pirfenidone-naïve group, N = 64) revealed that body weight, BMI, %FVC, and %DLco were significantly lower in the switch-group than in the pirfenidone-naïve group (Table 6). Conversely, the incidence of nintedanib-induced anorexia was significantly higher in the switch-group than in the pirfenidone-naïve group (p = 0.028). Moreover, nintedanib-induced anorexia tended to be more severe in the switch-group than in the pirfenidone-naïve group (Table 7). The proportion of discontinuation of nintedanib within 6 months was also higher in the switch-group than in the pirfenidone-naïve group, although this difference did not reach statistical significance (p = 0.0720). However, just before initiating pirfenidone, patients in the switch-group had approximately the same body weight, BMI, BSA, FVC, and DLco values as the baseline values of the pirfenidone-naïve group.