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

Disclosures

BMC Pulm Med. 2019;19(78) 

In This Article

Discussion

In the present study, as many as 53.3% of patients discontinued nintedanib within 6 months after switching from pirfenidone. Although risk factors for the early termination of nintedanib in IPF patients have not been fully investigated, the present study demonstrated the following two important clinical observations; first, low BMI was a risk factor for the early termination of nintedanib in the switch group; second, nintedanib-induced anorexia was more frequent and severer in the switch-group than in the pirfenidone-naïve group, but no significant differences were observed in terms of other AEs.

The present study suggested that a small physique can predict the early termination of nintedanib. In fact, the incidence of early termination of nintedanib in the present study was considerably higher than that in the INPULSIS trials, whereas values of physique-related factors, such as body weight, BMI, and absolute FVC, were considerably lower than those reported in the INPULSIS trials. Similarly, in the present study, the incidence of early termination of nintedanib was higher in the switch-group than in the pirfenidone-naïve group, whereas the values of physique-related factors were significantly lower in the switch-group than in the pirfenidone-naïve group. Interestingly, just before initiating pirfenidone, patients in the switch group had approximately the same body weight, BMI, BSA, and absolute FVC values as the baseline values of the pirfenidone-naïve group. This down-sizing of physique in the present study might have been due to not only the disease progression but also pirfenidone-induced weight loss, and this would be a major problem in the treatment sequence from pirfenidone to nintedanib.

Furthermore, the high incidence of early termination in patients with a small physique may have been because of the increase in the incidence and severity of AEs. We previously reported that a high incidence of hepatotoxicity resulting in treatment interruption was noted in IPF patients treated with nintedanib at our hospital.[16] In this study, small physique was associated with the hepatotoxicity of nintedanib in IPF patients. Similarly, despite the relatively short observation period of the present study, the incidence and severity of nintedanib-induced AEs, such as AST/ALT elevation and anorexia, tended to be higher in this study than in the INPULSIS trials. A pharmacokinetic study confirmed that body weight is a statistically significant covariate that influences nintedanib exposure.[17] Based on these results, we speculated that small patients tended to have a high serum concentration, and were therefore more likely to develop AEs. Careful monitoring of AEs and dose adjustment of nintedanib is required especially for the small patients.

However, although the values of physique-related factors were significantly lower in the switch-group than in the pirfenidone-naïve group in the present study, only nintedanib-induced anorexia was significantly more frequent and severer in the switch-group than in the pirfenidone-naïve group, whereas no significant differences were observed in other AEs such as diarrhea and AST/ALT elevation. During the pirfenidone administration period before being switched to nintedanib, 53.3% of patients exhibited anorexia with a CTCAE grade of ≥2, and 56.7% of patients exhibited weight loss of ≥5% from baseline. Nevertheless, 76.6% of patients were switched to nintedanib with an interruption period of less than 1 month. The anorexia and weight loss occurring during the pirfenidone administration period persist until nintedanib initiation and might affect the incidence and severity of anorexia during the subsequent nintedanib treatment. In fact, among 14 patients who developed anorexia during the nintedanib administration period in the switch group, 11 patients (78.6%) have already experienced anorexia during prior pirfenidone treatment. Furthermore, in the switch group of the present study, anorexia along with weight loss was one of the most common immediate causes of nintedanib discontinuation (Table 3), and this might also be the underlying cause of deterioration in physical condition or death. With regard to body weight loss, this could be an independent factor for decreased survival of IPF.[18] Thus, careful monitoring of body weight and the maintenance of nutritional status is mandatory in patients receiving anti-fibrotic therapies.

It is also noteworthy that nintedanib suppressed FVC decline compared with pirfenidone in 70% of patients who could undergo lung function tests before and after switching to nintedanib. As indicated both in a previous case series[7] and the present study, the intra-individual response to the two anti-fibrotic drugs may differ, and nintedanib is expected to suppress disease progression even after deterioration during the pirfenidone administration period. However, our results indicated that pirfenidone administration continued until the appearance of anorexia with a CTCAE grade of ≥2 or weight loss is inappropriate to maximally utilize subsequent nintedanib. Considering that gastrointestinal AEs tended to occur early in the treatment course (< 6 months) of pirfenidone,[19] dose modification or symptomatic therapy is required during this period.[20] When the gastrointestinal AEs of pirfenidone cannot be adequately managed, clinicians should consider switching to nintedanib early, although continued treatment with pirfenidone may suppress further FVC decline and/or death even in patients with IPF who exhibit meaningful disease progression during treatment.[21] Moreover, when clinicians consider switching from pirfenidone to nintedanib due to gastrointestinal AEs, it would probably be better to have a certain washout period.

Recently, several clinical trials of the combined use of pirfenidone and nintedanib, which mainly evaluated the safety and pharmacokinetics, have been reported.[22–24] To proficiently use two anti-fibrotic drugs, there is a need to accumulate more cases and conduct further research into combination therapy or a treatment sequence involving nintedanib followed by pirfenidone administration.

A limitation of the present study was the retrospective single-center study design. Additionally, the number of included patients was small and the distribution of patients may have been skewed. There is a need to accumulate more cases from several hospitals and conduct further investigations for the validation of the present results. The short observation period was also a limitation when assessing long-term safety. Moreover, we didn't set specific criteria for the FVC decline to consider switching from pirfenidone to nintedanib in our center, thus leaving the attending physicians to determine whether pirfenidone treatment is to be continued or changed.

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