Nintedanib y pirfenidona en el tratamiento farmacológico de la fibrosis pulmonar idiopática: perspectivas actuales y futuras. / Nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis: current and future perspectives.
Abstract
Resumen.
La fibrosis pulmonar idiopática es una enfermedad progresiva y fatal. En los últimos años se han identificado algunos factores involucrados en el desarrollo de la lesión del epitelio alveolar y en el remodelado anormal que conducen a la fibrosis, los cuales han sido evaluados para el desarrollo de tratamientos específicos. Dos terapias modificadoras de la enfermedad, pirfenidona y nintedanib, han demostrado reducir la progresión de la enfermedad, en términos de disminución de la capacidad vital forzada, con un efecto limítrofe sobre la mortalidad. Estos medicamentos han sido aprobados para su uso en pacientes con deterioro leve a moderado de la función pulmonar. Estudios de la vida real han evaluado estos tratamientos en poblaciones no representadas en los ensayos clínicos, con beneficios, seguridad y tolerancia similares. Los medicamentos difieren en su perfil de seguridad, pero ninguno ha demostrado ser mejor al otro en términos de eficacia. La decisión de comenzar estos tratamientos debe ponderar la gravedad de la enfermedad y las expectativas y preferencias del paciente. El tratamiento farmacológico combinado posiblemente será el tratamiento estándar en el futuro, pero nuevos estudios deberán evaluar su eficacia.
Abstract.
Idiopathic pulmonary fibrosis is a progressive and fatal disease. In recent years, some factors involved in the pathophysiology of the alveolar epithelial injury and in the abnormal remodeling that lead to fibrosis have been identified, some factors involved in the pathophysiology of the alveolar epithelial injury and in the abnormal remodeling that lead to fibrosis have been identified, some of them have been evaluated for the development of specific treatments. Two disease-modifying therapies, pirfenidone and nintedanib, have demonstrated to reduce the progression of the disease, in terms of decline in forced vital capacity, with a borderline effect on mortality. These drugs have been approved for patients with mild to moderate impairment in pulmonary function tests. Real-life studies have evaluated these treatments in populations not represented in clinical trials, with similar benefits, safety and tolerance. Pirfenidone and nintedanib have different safety profiles, but none is better in terms efficacy. Decision to start treatment should weight the severity of the disease and the patient’s expectations and preferences. Combined drug treatment possibly will be the standard of treatment in the future, but further studies must assess its efficacy.
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Raghu G, Rochwerg B, Zhang Y, Garcia CAC, Azuma A, Behr J, Brozek JL, Co- llard HR, Cunningham W, Homma S, Jo- hkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A, Wells AU, Hoogsteden H, Schünemann HJ; American Thoracic Society; European Respiratory society; Japanese Respiratory Society; Latin American Thoracic Asso- ciation. An official ATS/ERS/JRS/ALAT clinical practice guideline: Treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 2015; 192: e3-e19.
Richeldi L, Collard HR, Jones MG. Idio- pathic pulmonary fibrosis. Lancet 2017; 389: 1941–1952.
Selman M, Pardo A. Revealing the patho- genic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. An integral model. Am J Respir Crit Care Med 2014; 189: 1161–1172.
Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S , Kolb M. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015; 45: 1434–1445.
Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Pred- nisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366: 1968–1977.
Xaubet A, Serrano-Mollar A, Ancochea J. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Pharma- cother 2014; 15: 275–281.
Antoniou KM, Wuyts W, Wijsenbeek M, Wells AU. Medical therapy in idiopathic pulmonary fibrosis. Semin Respir Crit Care Med 2016; 37: 368–377.
Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, Sato A, Kudoh S. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibro- sis. Am J Respir Crit Care Med 2005; 171: 1040–1047.
Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, Takeuchi M, Raghu G, Kudoh S, Nukiwa T; Pirfenidone Clini- cal Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: 821–829.
Noble PW, Albera C, Bradford WZ, Costa- bel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM; CAPACITY Stu- dy Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–1769.
King TE Jr, Bradford WZ, Castro-Bernar- dini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083–2092.
Noble PW, Albera C, Bradford WZ, Cos- tabel U, du Bois RM, Fagan EA, Fishman RS, Glaspole I, Glassberg MK, Lancaster L, Lederer DJ, Leff JA, Nathan SD, Pereira CA, Swigris JJ, Valeyre D, King TE Jr. Pir- fenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multina- tional phase 3 trials. Eur Respir J 2016; 47: 243–253.
Nathan SD, Albera C, Bradford WZ, Cos- tabel U, Glaspole I, Glassberg MK, Kar- datzke DR, Daigl M, Kirchgaessler KU, Lancaster LH, Lederer DJ, Pereira CA, Swigris JJ, Valeyre D, Noble PW. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idio- pathic pulmonary fibrosis. Lancet Respir Med 2017; 5: 33–41.
Ley B, Swigris J, Day B-M, Stauffer JL, Raimundo K, Chou W, Collard HR. Pirfe- nidone reduces respiratory-related hospi- talizations in idiopathic pulmonary fibro- sis. Am J Respir Crit Care Med 2017; 196: 756–761.
Aravena C, Labarca G, Venegas C, Are- nas A, Rada G. Pirfenidone for idiopathic pulmonary fibrosis: A systematic review and meta-analysis. PloS One 2015; 10: e0136160.
Fisher M, Nathan SD, Hill C, Marshall J, Dejonckheere F, Thuresson PO, Maher TM. Predicting life expectancy for pirfenidone in idiopathic pulmonary fibrosis. J Manag Care Spec Pharm 2017; 23: S17–S24.
Albera C, Costabel U, Fagan EA, Glassberg MK, Gorina E, Lancaster L, Lederer DJ, Nathan SD, Spirig D, Swigris JJ. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function. Eur Respir J 2016; 48: 843–851.
Nathan SD, Albera C, Bradford WZ, Cos- tabel U, du Bois RM, Fagan EA, Fishman RS, Glaspole I, Glassberg MK, Glasscock KF, King TE Jr, Lancaster L, Lederer DJ, Lin Z, Pereira CA, Swigris JJ, Valeyre D, Noble PW, Wells AU. Effect of continued treatment with pirfenidone following clini- cally meaningful declines in forced vital ca- pacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax 2016; 71: 429–435.
Torrisi SE, Pavone M, Vancheri A, Vancheri C. When to start and when to stop antifibro- tic therapies. Eur Respir Rev 2017; 26: pii: 170053.
Costabel U, Bendstrup E, Cottin V, Dewint P, Egan JJ, Ferguson J, Groves R, Hellström PM, Kreuter M, Maher TM, Molina-Molina M, Nordlind K, Sarafidis A, Vancheri C. Pirfenidone in idiopathic pul- monary fibrosis: expert panel discussion on the management of drug-related adverse events. Adv Ther 2014; 31: 375–391.
Lancaster L, Albera C, Bradford WZ, Cos- tabel U, du Bois RM, Fagan EA, Fishman RS, Glaspole I, Glassberg MK, King TE Jr, Lederer DJ, Lin Z, Nathan SD, Pereira CA, Swigris JJ, Valeyre D, Noble PW. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. BMJ Open Respir Res 2016; 3: e000105.
Arai T, Inoue Y, Sasaki Y, Tachibana K, Nakao K, Sugimoto C, Okuma T, Akira M, Kitaichi M, Hayashi S. Predictors of the clinical effects of pirfenidone on idiopathic pulmonary fibrosis. Respir Investig 2014; 52: 136–143.
Behr J, Bendstrup E, Crestani B, Günther A, Olschewski H, Sköld CM, Wells A, Wu- yts W, Koschel D, Kreuter M, Wallaert B, Lin CY, Beck J, Albera C. Safety and to- lerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmo- nary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 2016; 4: 445–453.
Keating GM. Nintedanib: A review of its use in patients with idiopathic pulmonary fibro- sis. Drugs 2015; 75: 1131–1140.
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klüglich M, du Bois RM. Efficacy of a tyrosine kinase in- hibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079–1087.
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Fla- herty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Gi- rard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial In- vestigators. Efficacy and safety of ninteda- nib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071–2082.
Costabel U, Inoue Y, Richeldi L, Collard HR, Tschoepe I, Stowasser S, Azuma A. Efficacy of nintedanib in idiopathic pulmo- nary fibrosis across prespecified subgroups in INPULSIS. Am J Respir Crit Care Med 2016; 193: 178–185.
Raghu G, Wells AU, Nicholson AG, Richel- di L, Flaherty KR, Le Maulf F, Stowasser S, Schlenker-Herceg R, Hansell DM. Effect of nintedanib in subgroups of idiopathic pul- monary fibrosis by diagnostic criteria. Am J Respir Crit Care Med 2017; 195: 78–85.
Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S, Hallmann C, du Bois RM. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volu- me. Thorax 2017; 72: 340–346.
Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, Schlenker-Herceg R, Stowasser S, Brown KK. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med 2016; 113: 74–79.
Richeldi L, Kreuter M, Selman M, Cresta- ni B, Kirsten AM, Wuyts WA, Xu Z, Bernois K, Stowasser S, Quaresma M, Costabel U. Long-term treatment of patients with idio- pathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax 2018; 73: 581–583.
Wuyts WA, Kolb M, Stowasser S, Stansen W, Huggins JT, Raghu G. First data on effi- cacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis and for- ced vital capacity of ≤50 % of predicted va- lue. Lung 2016; 194: 739–743.
Corte T, Bonella F, Crestani B, Demedts MG, Richeldi L, Coeck C, Pelling K, Qua- resma M, Lasky JA. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res 2015; 16: 116.
Harari S, Caminati A. Idiopathic pulmo- nary fibrosis: from clinical trials to real- life experiences. Eur Respir Rev 2015; 24: 420–427.
Ogura T, Azuma A, Inoue Y, Taniguchi H, Chida K, Bando M, Niimi Y, Kakutani S, Suga M, Sugiyama Y, Kudoh S, Nukiwa T. All-case post-marketing surveillance of 1371 patients treated with pirfenidone for idiopathic pulmonary fibrosis. Respir Inves- tig 2015; 53: 232–241.
Hughes G, Toellner H, Morris H, Leonard C, Chaudhuri N. Real world experiences: Pirfenidone and nintedanib are effective and well tolerated treatments for idiopathic pulmonary fibrosis. J Clin Med 2016; 5: pii: E78.
Oltmanns U, Kahn N, Palmowski K, Träger A, Wenz H, Heussel CP, Schnabel PA, Pu- derbach M, Wiebel M, Ehlers-Tenenbaum S, Warth A, Herth FJ, Kreuter M. Pirfeni- done in idiopathic pulmonary fibrosis: real- life experience from a German tertiary re- ferral center for interstitial lung diseases. Respiration 2014; 88: 199–207.
Bonella F, Kreuter M, Hagmeyer L, Neu- rohr C, Keller C, Kohlhaeufl MJ, Müller- Quernheim J, Milger K, Prasse A; German Nintedanib Compassionate Use Consor- tium. Insights from the German compas- sionate use program of nintedanib for the treatment of idiopathic pulmonary fibrosis. Respiration 2016; 92: 98–106.
Galli JA, Pandya A, Vega-Olivo M, Dass C, Zhao H, Criner GJ. Pirfenidone and nin- tedanib for pulmonary fibrosis in clinical practice: Tolerability and adverse drug re- actions. Respirology 2017; 22: 1171–1178.
Tabaj GC, Sivori M, Cornejo L, Plotquin Experiencia en la Argentina del Pro- grama de uso compasivo con nintedanib en el tratamiento de la Fibrosis Pulmonar Idiopática. Rev Am Med Respir 2017; 17: 126–130.
National Institute for Health and Care Ex- cellence. Nintedanib for treating idiopathic pulmonary fibrosis. NICE Guidance and guidelines [Internet] 2016 [cited 2018 Feb 11]. Available from: URL:https://www.nice. org.uk/guidance/ta379
National Institute for Health and Care Excellence. Pirfenidone for treating idio- pathic pulmonary fibrosis. NICE Guidance and guidelines [Internet] 2018 [cited 2018 Feb 11]. Available from: URL:https://www. nice.org.uk/guidance/ta504
Xaubet A, Molina-Molina M, Acosta O, Bollo E, Castillo D, Fernández-Fabrellas E, Rodríguez-Portal JA, Valenzuela C, Ancochea J. Guidelines for the medical treatment of idiopathic pulmonary fibrosis. Arch Bronconeumol 2017; 53: 263–269.
Asociación Latino Americana de Tórax. Recomendaciones para el diagnóstico y tratamiento de la Fibrosis Pulmonar Idio- pática [Internet] 2015 [cited 2018 Jan 9]. Available from: URL:https://alatorax.org/ es/recomendaciones/recomendaciones-pa- ra-el-diagnostico-y-tratamiento-de-la-fibro- sis-pulmonar-idiopatica-2015
Loveman E, Copley VR, Colquitt JL, Scott DA, Clegg AJ, Jones J, O’Reilly KM, Singh S, Bausewein C, Wells A. The effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: systematic review, network meta-analysis and health economic evaluation. BMC Pharmacol Toxi- col 2014; 15: 63.
Loveman E, Copley VR, Scott DA, Col- quitt JL, Clegg AJ, O’Reilly KM. Compa- ring new treatments for idiopathic pulmo- nary fibrosis--a network meta-analysis. BMC Pulm Med 2015; 15: 37.
Rogliani P, Calzetta L, Cavalli F, Matera MG, Cazzola M. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Pulm Pharmacol Ther 2016; 40: 95–103.
Canestaro WJ, Forrester SH, Raghu G, Ho L, Devine BE. Drug treatment of idiopathic pulmonary fibrosis: Systematic review and network meta-analysis. Chest 2016; 149: 756–766.
Rochwerg B, Neupane B, Zhang Y, Garcia CC, Raghu G, Richeldi L, Brozek J, Be- yene J, Schünemann H. Treatment of idio- pathic pulmonary fibrosis: a network meta- analysis. BMC Med 2016; 14: 18.
Fleetwood K, McCool R, Glanville J, Ed- wards SC, Gsteiger S, Daigl M, Fisher Systematic review and network meta- analysis of idiopathic pulmonary fibrosis treatments. J Manag Care Spec Pharm 2017; 23: S5–S16.
Durheim MT, Collard HR, Roberts RS, Brown KK, Flaherty KR, King TE Jr, Pal- mer SM, Raghu G, Snyder LD, Anstrom KJ, Martinez FJ; IPFnet investigators. Association of hospital admission and for- ced vital capacity endpoints with survival in patients with idiopathic pulmonary fibro- sis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med 2015; 3: 388–396.
King CS, Nathan SD. POINT: Should all pa- tients with idiopathic pulmonary fibrosis, even those with more than moderate im- pairment, be treated with nintedanib or pir- fenidone? Yes. Chest 2016; 150: 273–275.
Pozo L, Paladio-Hernández J. Cost-effec- tive evaluation of pirfenidone for treating idiopathic pulmonary fibrosis in Mexico. Va- lue Health 2015; 18: A840-A841.
Ho R, Rufino C, Lisondo C, Alves M. Cost- effectiveness analysis of pirfenidone versus nintedanib on the treatment of idiopathic pulmonary fibrosis. Value Health 2017; 20: A893–A894.
Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, Bando M, Abe S, Mochizuki Y, Chida K, Klüglich M, Fujimo- to T, Okazaki K, Tadayasu Y, Sakamoto W, Sugiyama Y. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2015; 45: 1382–1392.
Vancheri C, Kreuter M, Richeldi L, Ryer- son CJ, Valeyre D, Grutters JC, Wiebe S, Stansen W, Quaresma M, Stowasser S, Wu- yts WA; INJOURNEY Trial Investigators. Nintedanib with add-on pirfenidone in idio- pathic pulmonary fibrosis. Results of the INJOURNEY trial. Am J Respir Crit Care Med 2018; 197: 356–363.
Nathan SD, Shlobin OA, Weir N, Ahmad S, Kaldjob JM, Battle E, Sheridan MJ, du Bois RM. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest 2011; 140: 221–229.
Brown KK. COUNTERPOINT: Should all pa- tients with idiopathic pulmonary fibrosis, even those with more than moderate im- pairment, be treated with nintedanib or pir- fenidone? No. Chest 2016; 150: 276–278.
Ferrara G, Luppi F, Birring SS, Cerri S, Caminati A, Sköld M, Kreuter M. Best sup- portive care for idiopathic pulmonary fibro- sis: current gaps and future directions. Eur Respir Rev 2018; 27: pii: 170076.
Kulkarni T, Willoughby J, Acosta Lara MDP, Kim Y-I, Ramachandran R, Alexan- der CB, Luckhardt T, Thannickal VJ, de Andrade JA. A bundled care approach to patients with idiopathic pulmonary fibro- sis improves transplant-free survival. Respir Med 2016; 115: 33–38.
Buendía-Roldán I, Mejía M, Navarro C, Selman M. Idiopathic pulmonary fibrosis: Clinical behavior and aging associated co- morbidities. Respir Med 2017; 129: 46–52.
