pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2017-27-6-789-802pulmo-947Research ArticleОБЗОРЫREVIEWСравнительная клинико-фармакологическая характеристика современных антифибротических препаратов, рекомендованных для фармакотерапииClinical and pharmacological comparison of current antifibrotic drugs for therapy of idiopathic pulmonary fibrosisЗыряновС. К.ZyryanovS. K.

Зырянов Сергей Кенсаринович – доктор медицинских наук, профессор, заведующий кафедрой общей и клинической фармакологии 

117198, Москва, ул. Миклухо-Маклая, 6

Sergey K. Zyryanov, Doctor of Medicine, Professor, Head of Department of General and Clinical Pharmacology, Medical Institute 

ul. Miklukho-Maklaya 6, Moscow, 117198, Russia;

zyryanov_sk@rudn.universityБутрановаО. И.ButranovaO. I.

Бутранова Ольга Игоревна – кандидат медицинских наук, ассистент кафедры общей и клинической фармакологи 

117198, Москва, ул. Миклухо-Маклая, 6

Ol'ga I. Butranova, Candidate of Medicine, Assistant Lecturer, Department of General and Clinical Pharmacology, Medical Institute 

ul. Miklukho-Maklaya 6, Moscow, 117198, Russia;

butranovaolga@mail.ruШаталоваО. В.ShatalovaO. V.

Шаталова Ольга Викторовна – кандидат медицинских наук ассистент кафедры клинической фармакологии и интенсивной терапии с курсами клинической фармакологии и клинической аллергологии факультета усовершенствования врачей 

400008, Волгоград, пл. Павших Борцов, 1

Ol'ga V. Shatalova, Candidate of Medicine, Assistant Lecturer, Department of Clinical Pharmacology and Intensive Care with the Course of Clinical Pharmacology and Clinical Allergology, Faculty of Postgraduate Physician Training 

 pl. Pavshikh Bortsov 1, Volgograd, 400008, Russia

shov_med@mail.ruФедеральное государственное автономное образовательное учреждение высшего образования «Российский университет дружбы народов» (Медицинский институт)РоссияPeoples' Friendship University of Russia:Russian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияPeoples' Friendship University of Russia:Russian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияFederal Volgograd State Medical University, Healthcare Ministry of RussiaRussian Federation201723022018276789802Copyright © Зырянов С.К., Бутранова О.И., Шаталова О.В., 20182018Зырянов С.К., Бутранова О.И., Шаталова О.В.Zyryanov S.K., Butranova O.I., Shatalova O.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/947

В последнее десятилетие возможности фармакотерапии идиопатического легочного фиброза (ИЛФ) благодаря внедрению в клиническую практику лекарственных препаратов, обладающих доказанной̆ эффективностью, – нинтеданиба и пирфенидона – значительно расширились. По результатам завершенных рандомизированных клинических исследований (РКИ) III фазы продемонстрирована способность указанных препаратов замедлять прогрессирование ИЛФ и снижать смертность от всех причин по сравнению с плацебо. Прямые сравнения эффективности и безопасности режимов фармакотерапии с использованием пирфенидона и нинтеданиба у больных ИЛФ в настоящее время отсутствуют. По результатам объединенного анализа исследований INPULSIS-1, INPULSIS-2 и TOMORROW, посвященных нинтеданибу, относительный риск (ОР) смертности составил 0,70 (95%-ный доверительный интервал – 0,47–1,03), а по результатам объединенного анализа исследований CAPACITY-1, CAPACITY-2 и ASCEND, в которых изучалось действие пирфенидона, ОР также составил 0,70 (95%-ный ДИ – 0,47–1,02). Однако дизайн проведенных РКИ, в которых оценивалась клиническая эффективность нинтеданиба и пирфенидона, не был ориентирован на исследование смертности как первичной конечной точки, которой во всех исследованиях являлось изменение показателей форсированной жизненной емкости легких. По результатам имеющихся на сегодняшний день данных метаанализов продемонстрирован сходный эффект как нинтеданиба, так и пирфенидона в отношении показателей смертности от всех причин и смертности, связанной с респираторными причинами при доказанном положительном эффекте на течение и прогрессирование ИЛФ.

Therapeutic options for idiopathic pulmonary fibrosis (IPF) have been significantly extended last decade due to clinical use of drugs with confirmed antifibrotic activity, nintedanib and pirfenidone. Results of completed randomized phase III clinical trials (RCT) showed the ability of these drugs to decrease IPF progression and all-cause mortality compared to placebo. No direct comparison of efficacy and safety of different pharmacotherapeutic regimens with nintedanib and pirfenidone in IPF patients was published. The pooled odds ratio for mortality was 0.70 (95% confidential interval (CI), 0.47–1.03) in three trials of nintedanib (INPULSIS-1, INPULSIS-2, and TOMORROW; 2015) and 0.70 (0.47–1.02) in three trials of pirfenidone (CAPACITY-1, CAPACITY-2, and ASCEND). RCTs evaluating clinical efficacy of nintedanib and pirfenidone were not designed to assessment of mortality as the primary end-point; the primary end-point in all the trials was the change in the forced vital capacity of the lungs. Published metaanalyses demonstrated similar effects of nintedanib and pirfenidone on all-cause mortality and mortality from respiratory causes and confirmed favourable effects of both the drugs on course and progression of IPF.

идиопатический легочный фиброзантифибротические препаратынинтеданибпирфенидонidiopathic pulmonary fibrosisantifibrotic drugsnintedanibpirfenidoneReferencesRaghu G., Collard H.R., Egan J.J. et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis; evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 2011; 183 (6): 788–824. DOI: 10.1164/rccm.2009-040GL.Raghu G., Collard H.R., Egan J.J. et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis; evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 2011; 183 (6): 788–824. DOI: 10.1164/rccm.2009-040GL.Raghu G., Rochwerg B., Zhang Yu. et al. 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: (2) 3–19. DOI: 10.1164/rccm.201506-1063ST.Raghu G., Rochwerg B., Zhang Yu. et al. 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: (2) 3–19. DOI: 10.1164/rccm.201506-1063ST.Travis W.D., Costabel U., Hansell D.M. et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am. J. Respir. Crit. Care Med. 2013; 188 (6): 733–748. DOI: 10.1164/rccm.201308-1483ST.Travis W.D., Costabel U., Hansell D.M. et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am. J. Respir. Crit. Care Med. 2013; 188 (6): 733–748. DOI: 10.1164/rccm.201308-1483ST.Ryu J.H., Moua T., Daniels C.E. et al. Idiopathic pulmonary fibrosis: evolving concepts. Mayo Clin. Proc. 2014; 89: (8) 1130–1142. DOI: 10.1016/j.mayocp.2014.03.016.Ryu J.H., Moua T., Daniels C.E. et al. Idiopathic pulmonary fibrosis: evolving concepts. Mayo Clin. Proc. 2014; 89: (8) 1130–1142. DOI: 10.1016/j.mayocp.2014.03.016.Raghu G., Weycker D., Edelsberg J. et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2006; 174 (7): 810–816. DOI: 10.1164/rccm.200602-163OC.Raghu G., Weycker D., Edelsberg J. et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2006; 174 (7): 810–816. DOI: 10.1164/rccm.200602-163OC.Richeldi L., Rubin A.S., Avdeev S. et al. Idiopathic pulmonary fibrosis in BRIC countries: the cases of Brazil, Russia, India, and China. BMC Medicine. 2015; 13: 237. DOI: 10.1186/s12916-015-0495-0.Richeldi L., Rubin A.S., Avdeev S. et al. Idiopathic pulmonary fibrosis in BRIC countries: the cases of Brazil, Russia, India, and China. BMC Medicine. 2015; 13: 237. DOI: 10.1186/s12916-015-0495-0.Meltzer E.B., Noble P.W. Idiopathic pulmonary fibrosis. Orphanet. J. Rare Dis. 2008; 3: 8. DOI: 10.1186/1750-1172-3-8.Meltzer E.B., Noble P.W. Idiopathic pulmonary fibrosis. Orphanet. J. Rare Dis. 2008; 3: 8. DOI: 10.1186/1750-1172-3-8.Чучалин А.Г., Авдеев С.Н., Айсанов З.Р. и др. Диагностика и лечение идиопатического легочного фиброза. Федеральные клинические рекомендации. Пульмонология. 2016; 26 (4): 399–419. DOI: 10.18093/0869-0189-2016-26-4-399-419.Chuchalin A.G., Avdeev S.N., Aisanov Z.R. et al. Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis. Federal Guidelines. Pul'monologiya. 2016; 26 (4): 399–419. DOI: 10.18093/0869-0189-2016-26-4-399-419 (in Russian).Davies H.R., Richeldi L., Walters E.H. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst. Rev. 2003; 3: CD003134. DOI: 10.1002/14651858.CD003134.Davies H.R., Richeldi L., Walters E.H. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst. Rev. 2003; 3: CD003134. DOI: 10.1002/14651858.CD003134.von Suesskind-Schwendi M., Boxhammer E., Hirt S.W. et al. The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection. Exp. Lung Res. 2017; 43 (6-7): 259–270. DOI: 10.1080/01902148.2017.1354408.von Suesskind-Schwendi M., Boxhammer E., Hirt S.W. et al. The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection. Exp. Lung Res. 2017; 43 (6-7): 259–270. DOI: 10.1080/01902148.2017.1354408.Flaherty K.R., Toews G.B., Lynch J.P. 3rd et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am. J. Med. 2001; 110 (4): 278–282. DOI: 10.1016/S0002-9343(00)00711-7.Flaherty K.R., Toews G.B., Lynch J.P. 3rd et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am. J. Med. 2001; 110 (4): 278–282. DOI: 10.1016/S0002-9343(00)00711-7.Raghu G., Anstrom K.J., King T.E. Jr et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 2012; 366 (21): 1968–1977. DOI: 10.1056/NEJMoa1113354.Raghu G., Anstrom K.J., King T.E. Jr et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 2012; 366 (21): 1968–1977. DOI: 10.1056/NEJMoa1113354.Martinez F.J., de Andrade J.A., Anstrom K.J. et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2093–2101. DOI: 10.1056/NEJMoa1401739.Martinez F.J., de Andrade J.A., Anstrom K.J. et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2093–2101. DOI: 10.1056/NEJMoa1401739.King T.E. Jr, Bradford W.Z., Castro-Bernardini S. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2083–2092. DOI: 10.1056/NEJMoa1402582.King T.E. Jr, Bradford W.Z., Castro-Bernardini S. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2083–2092. DOI: 10.1056/NEJMoa1402582.Richeldi L., du Bois R.M., Raghu G. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2071–2082. DOI: 10.1056/NEJMoa1402584.Richeldi L., du Bois R.M., Raghu G. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2071–2082. DOI: 10.1056/NEJMoa1402584.Wollin L., Maillet I., Quesniaux V. et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J. Pharmacol. Exp. Ther. 2014; 349 (2): 209–220. DOI: 10.1124/jpet.113.208223.Wollin L., Maillet I., Quesniaux V. et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J. Pharmacol. Exp. Ther. 2014; 349 (2): 209–220. DOI: 10.1124/jpet.113.208223.Hilberg F., Roth G.J., Krssak M. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008; 68 (12):4774–4782. DOI: 10.1158/0008-5472.CAN-07-6307.Hilberg F., Roth G.J., Krssak M. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008; 68 (12):4774–4782. DOI: 10.1158/0008-5472.CAN-07-6307.Sundarakrishnan A., Chen Y., Black L.D. et al. Engineered cell and tissue models of pulmonary fibrosis. Adv. Drug Deliv. Rev. 2017; Dec 18. pii: S0169-409X(17)30316-2. DOI: 10.1016/j.addr.2017.12.013. [Epub ahead of print].Sundarakrishnan A., Chen Y., Black L.D. et al. Engineered cell and tissue models of pulmonary fibrosis. Adv. Drug Deliv. Rev. 2017; Dec 18. pii: S0169-409X(17)30316-2. DOI: 10.1016/j.addr.2017.12.013. [Epub ahead of print].Fukihara J., Kondoh Y. Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis. Exp. Rev. Respir. Med. 2016; 10 (12): 1247–1254. DOI: 10.1080/17476348.2016.1249854.Fukihara J., Kondoh Y. Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis. Exp. Rev. Respir. Med. 2016; 10 (12): 1247–1254. DOI: 10.1080/17476348.2016.1249854.Schmid U., Doege C., Dallinger C., Freiwald M. Population pharmacokinetics of nintedanib in patients with idiopathic pulmonary fibrosis. Pulm. Pharmacol. Ther. 2018; 48: 136–143. DOI: 10.1016/j.pupt.2017.11.004.Schmid U., Doege C., Dallinger C., Freiwald M. Population pharmacokinetics of nintedanib in patients with idiopathic pulmonary fibrosis. Pulm. Pharmacol. Ther. 2018; 48: 136–143. DOI: 10.1016/j.pupt.2017.11.004.Woodcock H.V., Molyneaux P.L., Maher T.M. Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib. Drug Des. Dev. Ther. 2013; 7: 503–510. DOI: 10.2147/DDDT.S38833.Woodcock H.V., Molyneaux P.L., Maher T.M. Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib. Drug Des. Dev. Ther. 2013; 7: 503–510. DOI: 10.2147/DDDT.S38833.Schaefer C.J., Ruhrmund D.W., Pan L. et al. Antifibrotic activities of pirfenidone in animal models. Eur. Respir. Rev. 2011; 20 (120): 85–97. DOI: 10.1183/09059180.00001111.Schaefer C.J., Ruhrmund D.W., Pan L. et al. Antifibrotic activities of pirfenidone in animal models. Eur. Respir. Rev. 2011; 20 (120): 85–97. DOI: 10.1183/09059180.00001111.Macías-Barragán J., Sandoval-Rodríguez A., Navarro-Partida J., Armendáriz-Borunda J. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair. 2010; 3: 16. DOI: 10.1186/1755-1536-3-16.Macías-Barragán J., Sandoval-Rodríguez A., Navarro-Partida J., Armendáriz-Borunda J. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair. 2010; 3: 16. DOI: 10.1186/1755-1536-3-16.Taniguchi H., Ebina M., Kondoh Y. et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur. Respir. J. 2010; 35 (4): 821–829. DOI: 10.1183/09031936.00005209.Taniguchi H., Ebina M., Kondoh Y. et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur. Respir. J. 2010; 35 (4): 821–829. DOI: 10.1183/09031936.00005209.Rubino C.M., Bhavnani S.M., Ambrose P.G. et al. Effect of food and antiacids on the pharmacokinetics of pirfenidone in older healthy adults. Pulm. Pharmacol. Ther. 2009; 22 (4): 279–285. DOI: 10.1016/j.pupt.2009.03.003.Rubino C.M., Bhavnani S.M., Ambrose P.G. et al. Effect of food and antiacids on the pharmacokinetics of pirfenidone in older healthy adults. Pulm. Pharmacol. Ther. 2009; 22 (4): 279–285. DOI: 10.1016/j.pupt.2009.03.003.Noble P.W., Albera C., Bradford W.Z. et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011; 377 (9779): 1760–1769. DOI: 10.1016/S0140-6736(11)60405-4.Noble P.W., Albera C., Bradford W.Z. et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011; 377 (9779): 1760–1769. DOI: 10.1016/S0140-6736(11)60405-4.Fleetwood K., McCool R., Glanville J. et al. Systematic Review and Network Meta-analysis of Idiopathic Pulmonary Fibrosis Treatments. J. Manag. Care Spec. Pharm. 2017; 23 (3-b, Suppl.): S5–S16. DOI: 10.18553/jmcp.2017.23.3-b.s5.Fleetwood K., McCool R., Glanville J. et al. Systematic Review and Network Meta-analysis of Idiopathic Pulmonary Fibrosis Treatments. J. Manag. Care Spec. Pharm. 2017; 23 (3-b, Suppl.): S5–S16. DOI: 10.18553/jmcp.2017.23.3-b.s5.Canestaro W.J., Forrester S.H., Raghu G. et al. Drug treatment of idiopathic pulmonary fibrosis: a systematic review and network meta-analysis. Chest. 2016; 149 (3): 756–766. DOI: 10.1016/j.chest.2015.11.013.Canestaro W.J., Forrester S.H., Raghu G. et al. Drug treatment of idiopathic pulmonary fibrosis: a systematic review and network meta-analysis. Chest. 2016; 149 (3): 756–766. DOI: 10.1016/j.chest.2015.11.013.Rogliani P., Calzetta L., Cavalli F. et al. 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. DOI: 10.1016/j.pupt.2016.07.009.Rogliani P., Calzetta L., Cavalli F. et al. 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. DOI: 10.1016/j.pupt.2016.07.009.Crestani B., Kolb M., Wallaert B. et al. Long-Term Efficacy of Nintedanib Is Maintained in Patients with Idiopathic Pulmonary Fibrosis (IPF) Irrespective of Dose: Subgroup Analysis of INPULSIS-ON. Am. J. Respir. Crit. Care Med. 2017; 195: A5408.Crestani B., Kolb M., Wallaert B. et al. Long-Term Efficacy of Nintedanib Is Maintained in Patients with Idiopathic Pulmonary Fibrosis (IPF) Irrespective of Dose: Subgroup Analysis of INPULSIS-ON. Am. J. Respir. Crit. Care Med. 2017; 195: A5408.Richeldi L., Kreuter M., Selman M. et al. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax. 2017. Oct 9. pii: thoraxjnl-2016-209701. DOI: 10.1136/thoraxjnl-2016-209701. [Epub ahead of print].Richeldi L., Kreuter M., Selman M. et al. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax. 2017. Oct 9. pii: thoraxjnl-2016-209701. DOI: 10.1136/thoraxjnl-2016-209701. [Epub ahead of print].King T.E. Jr, Albera C., Bradford W.Z. et al. All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials. Am. J. Respir. Crit. Care Med. 2014; 189 (7): 825–831. DOI: 10.1164/rccm.201311-1951OC.King T.E. Jr, Albera C., Bradford W.Z. et al. All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials. Am. J. Respir. Crit. Care Med. 2014; 189 (7): 825–831. DOI: 10.1164/rccm.201311-1951OC.Loveman E., Copley V.R., Scott D.A. et al. Comparing new treatments for idiopathic pulmonary fibrosis – a network meta-analysis. BMC Pulm. Med. 2015; 15: 37. DOI: 10.1186/s12890-015-0034-y.Loveman E., Copley V.R., Scott D.A. et al. Comparing new treatments for idiopathic pulmonary fibrosis – a network meta-analysis. BMC Pulm. Med. 2015; 15: 37. DOI: 10.1186/s12890-015-0034-y.Rinciog C., Watkins M., Chang S. et al. A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK. PharmacoEconomics. 2017; 35 (4): 479–491. DOI: 10.1007/s40273-016-0480-2.Rinciog C., Watkins M., Chang S. et al. A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK. PharmacoEconomics. 2017; 35 (4): 479–491. DOI: 10.1007/s40273-016-0480-2.

The authors declare that there are no conflicts of interest present.