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Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra

Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Hiroki Yamamoto, Takeshi Yoshioka, Shuji Kaneko, Hirofumi Chiba
ERJ Open Research 2022 8: 00245-2022; DOI: 10.1183/23120541.00245-2022
Koji Kuronuma
1Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
4These authors contributed equally to first authorship
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  • For correspondence: kuronumak@sapmed.ac.jp
Natsumi Susai
2Biomarker R&D Department, Shionogi & Co., Ltd, Toyonaka, Japan
4These authors contributed equally to first authorship
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Tomohiro Kuroita
2Biomarker R&D Department, Shionogi & Co., Ltd, Toyonaka, Japan
3Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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Hiroki Yamamoto
3Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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Takeshi Yoshioka
2Biomarker R&D Department, Shionogi & Co., Ltd, Toyonaka, Japan
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Shuji Kaneko
3Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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Hirofumi Chiba
1Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
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  • FIGURE 1
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    FIGURE 1

    Concept of the real-world data analysis. The analytical concept to discover drug “A” is shown. The frequency of registered adverse effects in patients with pirfenidone (PFD) was compared with that in patients with PFD treated with drug “A”. When P>P′ was observed, drug “A” played a role in the development of adverse effects caused by PFD. A total of 11 428 031 reports from the US Food and Drug Administration Adverse Events Reporting System (FAERS) (from Quarter 1 2004 to Quarter 4 2019) were analysed. After identification of the name, 3568 types of medicines were investigated. The frequencies (%) of patients with and without PFD who suffered from photosensitivity were compared. Unknown drug–drug interactions against photosensitivity caused by PFD (figure 2a and b) and nausea caused by PFD or nintedanib (figure 2c and d) were evaluated in accordance with the Methods.

  • FIGURE 2
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    FIGURE 2

    Results of the real-world data analysis. The reported proportions of photosensitivity were compared between a) patients who used pirfenidone (PFD) and/or niacin and b) those who used PFD and/or a multivitamin preparation including niacin. Gastrointestinal events, such as nausea, fatigue, decreased appetite and diarrhoea, were compared between c) patients who used PFD and/or niacin and d) those who used nintedanib and/or niacin. *: significant difference (p<0.05); #: no significant difference, but there was a tendency; ns: nonsignificant.

  • FIGURE 3
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    FIGURE 3

    Pellagra-related photosensitivity caused by pirfenidone (PFD). Histological and clinical features of mice treated with or without PFD at day 16 are shown. a, c) Histological and clinical features of mice a) without or c) with ultraviolet (UV) irradiation at day 16. b) No dermal response, such as oedema (ear swelling) and erythema, was observed in mice fed the normal diet with PFD. d) Some dermal responses, such as oedema (ear swelling) and erythema, to UV irradiation were observed in mice fed the normal diet with PFD or the low-niacin diet with PFD. p-values are indicated. e) Skin levels of arachidonic acid (AA) metabolites were analysed by liquid chromatography-mass spectrometry-based methods in mice fed the normal diet (N) or the low-niacin diet (L) with 0 (vehicle), 1 or 3 mg PFD per mouse without UV irradiation (UV–) or with UV irradiation (UV+). Vertical bars indicate the percentage change in each metabolite versus the average of mice fed the normal diet with vehicle without UV irradiation (N0 UV–). The results of the statistical analysis are shown in supplementary table S1. Multiple comparisons were carried out by two-way ANOVA (Tukey–Kramer post hoc test). #: we focused on 18-hydroxyeicosatetraenoic acid (18-HETE), 11,12-dihydroxyeicosatrienoic acid (11,12-DHET) and 14,15-DHET. PG: prostaglandin; EET: epoxyeicosatrienoic acid. Data represent mean±se (n=5). Statistical analysis was carried out as described in the supplementary material. The experiments were repeated twice.

  • FIGURE 4
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    FIGURE 4

    Pellagra-related nausea caused by pirfenidone (PFD) (3 mg per mouse). a) Growth curves (body weight % change) in mice fed the normal diet with PFD or the low-niacin diet with PFD (n=5 in each group). b) Each comparison was carried out between both groups. AUC: area under the curve. c) The effect of pica on the shape of faeces from day 10 to 15 (D10–D15) was evaluated in mice treated with PFD kept under the low-niacin diet. Some faeces are indicated and pica began at 5 days onward after the first administration. d) Mice were kept under paper strips stained with carminic acid and coloured faeces were used to evaluate the severity of nausea. Some faeces from mice (n=4) at days 5 and 6 onwards are shown, and nausea severity (nausea score) was evaluated quantitatively using the coloured faeces (n=5). e) Multiple comparisons were carried out by two-way ANOVA (Tukey–Kramer post hoc test). Data are presented as mean±se (n=5). Statistical analysis was carried out as described in the supplementary material. The experiments were repeated twice.

  • FIGURE 5
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    FIGURE 5

    Mouse liver gene expression profiles. a) A cluster dendrogram from gene analysis was prepared to confirm genetic similarity among mice fed the low-niacin diet with vehicle or pirfenidone (PFD) (3 mg per mouse) and mice fed the normal diet with vehicle or PFD. b) Volcano plots between mice fed the normal diet with vehicle and those treated with PFD, mice fed the low-niacin diet with vehicle and those treated with PFD, mice fed the normal diet with vehicle and those fed the low-niacin diet, and mice fed the normal diet with PFD and those fed the low-niacin diet. Each dot represents one gene. Red dots indicate genes with significantly increased or decreased expression between the comparisons.

  • FIGURE 6
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    FIGURE 6

    Urine levels of niacin and its metabolites. The value (%) of each metabolite, based on metabolite/creatinine (Cre) ratios, was measured in mice fed the normal diet with pirfenidone (PFD) or low-niacin diet with PFD: a) day 15 and b) day 16. N0: normal diet with vehicle. c) The value (%) of each metabolite was measured in idiopathic pulmonary fibrosis patients (n=10 in each group). XA: xanthurenic acid; KA: kynurenic acid; NAM: nicotinamide; MNA: N-methylnicotinamide; 2-Py: Nʹ-methyl-2-pyridone-3-carboxamide; 4-Py: Nʹ-methyl-4-pyridone-3-carboxamide; NNO: nicotinamide-N-oxide; SAM: S-adenosylmethionine; Kyn: kynurenic acid; Trp: tryptophan; SAH: S-adenosylhomocysteine. Comparisons were carried out by one- or two-way ANOVA (Mann–Whitney test or Tukey–Kramer post hoc test). Data are presented as mean±se. Statistical analysis was carried out as described in the supplementary material. The mouse experiments were repeated twice.

Tables

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  • TABLE 1

    Baseline characteristics of the study subjects

    Without pirfenidoneWith pirfenidonep-value
    Subjects1010
    Age (years)72 (67–85)75.5 (67–88)0.1527
    Male/female8/28/2
    BMI (kg·m−2)26.2 (25.2–27.6)24.0 (21.6–25.8)0.1926
    Brinkman index800 (75–1743)900 (39.8–1490)0.6855
    VC (L)2.31 (2.07–3.09)2.61 (2.19–2.91)0.588
    VC (% pred)76.2 (68.3–92.2)80.9 (70.7–92.5)0.4608
    FVC (L)2.26 (1.97–3.08)2.64 (2.16–2.84)0.5236
    FEV1 (L)1.93 (1.72–2.46)2.34 (1.82–2.52)0.3674
    FEV1 (% pred)84.1 (77.2–89.3)85.8 (79.0–91.8)0.7371
    DLCO (mL·min−1·mmHg−1)12.9 (10.8–14.8)10.2 (9.3–13.3)0.3838
    DLCO (% pred)59.8 (53.5–71.3)43.6 (36.0–55.3)0.0369
    PaO2 (mmHg)89.1 (81.6–93.4)82.7 (77.6–88.3)0.2635
    PaCO2 (mmHg)38.9 (36.8–41.4)40.5 (39.4–43.7)0.1267
    SpO2min of 6MWT (%)92 (87.5–94)90 (87.5–95.3)0.861
    6MWD (m)430 (320–453)430 (358–485)0.6767
    SP-A (ng·mL−1)88.1 (46.6–111.7)70.7 (45.3–114.5)0.8306
    SP-D (ng·mL−1)323 (192.23–355.8)204.5 (114–314.5)0.2347
    KL-6 (U·mL−1)1100 (621.8–2218.8)1185 (803.8–1690)0.3867
    LDH (IU·L−1)255.5 (224.8–312)245 (223.3–300.3)0.8981

    Data are presented as n or median (interquartile range), unless otherwise stated. BMI: body mass index: VC: vital capacity; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; DLCO: diffusing capacity of the lung for carbon monoxide; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide tension; SpO2: oxygen saturation measured by pulse oximetry; 6MWT: 6-min walk test; 6MWD: 6-min walk distance; SP-A: surfactant protein A; SP-D: surfactant protein D; KL-6: Krebs von den Lungen-6; LDH: lactate dehydrogenase.

    • TABLE 2

      Main data from comprehensive genetic analysis

      ComparisonGeneLog2 (fold change)p-valueRanking#
      Normal/vehicle versus normal/PFDNnmt2.670.0000027
      Normal/vehicle versus low-niacin/vehicleNnmt1.870.0000532
      Normal/PFD versus low-niacin/PFDNeat11.990.000004
      Cyp7a1−1.990.000005
      Socs21.630.000027
      Idi1−1.580.000038
      Sult2a11.410.0000812
      Slc25a301.440.0001215
      Hgf−1.280.0009327
      Erbb4−1.510.0021237
      Fdps−1.010.0042749
      Low-niacin/vehicle versus low-niacin/PFDAlas13.820.000003
      Lpin13.400.000004
      Mt23.260.000006
      Dbp3.470.000008
      Chka−3.480.0000013
      Efna1−3.400.0000015
      Por2.520.0000017
      Socs22.680.0000019
      Per12.640.0000021
      Fkbp52.360.0000023
      Fmo32.210.0000026
      Pfkfb32.550.0000027
      Arntl−3.240.0000029
      Cebpb2.250.0000032
      Thrsp2.010.0000035
      Wee12.430.0000039
      St3gal51.900.0000040
      Gadd45g2.260.0000042
      Fmo51.850.0000043
      Angptl41.910.0000045
      Stbd11.720.0000150

      #: each gene was sorted by the p-value and the top 50 genes were ranked (supplementary tables S2–S5); the main genes of interest are listed here, ranked within each comparison. PFD: pirfenidone.

      Supplementary Materials

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        Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

        Supplementary material 00245-2022.SUPPLEMENT

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      Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra
      Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Hiroki Yamamoto, Takeshi Yoshioka, Shuji Kaneko, Hirofumi Chiba
      ERJ Open Research Oct 2022, 8 (4) 00245-2022; DOI: 10.1183/23120541.00245-2022

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      Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra
      Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Hiroki Yamamoto, Takeshi Yoshioka, Shuji Kaneko, Hirofumi Chiba
      ERJ Open Research Oct 2022, 8 (4) 00245-2022; DOI: 10.1183/23120541.00245-2022
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