, Volume 78, Issue 4, pp 399–410 | Cite as

Generic Substitution of Orphan Drugs for the Treatment of Rare Diseases: Exploring the Potential Challenges

  • Antonello Di Paolo
  • Elena Arrigoni
Current Opinion


Generic drugs are important components of measures introduced by healthcare regulatory authorities to reduce treatment costs. In most patients and conditions the switch from a branded drug to its generic counterpart is performed with no major complications. However, evidence from complex diseases suggests that generic substitution requires careful evaluation in some settings and that current bioequivalence criteria may not always be adequate for establishing the interchangeability of branded and generic products. Rare diseases, also called orphan diseases, are a group of heterogeneous diseases that share important characteristics: in addition to their scarcity, most are severe, chronic, highly debilitating, and often present in early childhood. Finding a treatment for a rare disease is challenging. Thanks to incentives that encourage research and development programs in rare diseases, several orphan drugs are currently available. The elevated cost of orphan drugs is a highly debated issue and a cause of limited access to treatment for many patients. As patent protection and the exclusivity period of several orphan drugs will expire soon, generic versions of orphan drugs should reach the market shortly, with great expectations about their impact on the economic burden of rare diseases. However, consistent with other complex diseases, generic substitution may require thoughtful considerations and may be even contraindicated in some rare conditions. This article provides an overview of rare disease characteristics, reviews reports of problematic generic substitution, and discusses why generic substitution of orphan drugs may be challenging and should be undertaken carefully in rare disease patients.



The author thanks Lorenza Lanini, an independent medical writer acting on behalf of Springer Healthcare Communications, who drafted the outline and first draft of this manuscript, as well as Matt Weitz of Springer Healthcare Communications for English editing and formatting of the manuscript for submission. Mimi Chan, PhD, of Springer Healthcare Communications, assisted with English editing of post-submission revisions. This editorial support was funded by Orphan Europe – Recordati Group.

Compliance with ethical standards


Orphan Europe-Recordati Group funded the assistance for medical writing.

Conflict of interest

ADP acted as advisory board member for Novartis Farma SpA.


  1. 1.
    US Food and Drug Administration (FDA). Facts about Generics. 2015. Accessed 9 Sep 2017.
  2. 2.
    Bate R, Mathur A, Lever HM, Thakur D, Graedon J, Cooperman T, et al. Generics substitution, bioequivalence standards, and international oversight: complex issues facing the FDA. Trends Pharmacol Sci. 2016;37:184–91. Scholar
  3. 3.
    Straka RJ, Keohane DJ, Liu LZ. Potential clinical and economic impact of switching branded medications to generics. Am J Ther. 2017;24:e278–89. Scholar
  4. 4.
    Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003;25:2875–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006;15:165–76. Scholar
  6. 6.
    de Vrueh R, Baekelandt ERF, de Haan JMH. Updated on Background Paper 6.19: Rare Diseases. World Health Organisation. 2013. Accessed 9 Sep 2017.
  7. 7.
    European Organisation for Rare Diseases (EURORDIS). Rare diseases in numbers: Preliminary report from an on going bibliographic study initiated by Eurordis in partnership with Orphanet. Accessed 9 Sep 2017.
  8. 8.
    European Organisation for Rare Diseases (EURORDIS). Rare diseases Europe: a factsheet. Accessed 9 Sep 2017.
  9. 9.
    Tambuyzer E. Rare diseases, orphan drugs and their regulation: questions and misconceptions. Nature Rev Drug Discov. 2010;9:921–9. Scholar
  10. 10.
    Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008;371:2039–41. Scholar
  11. 11.
    Miller KL, Lanthier M. Trends in orphan new molecular entities, 1983-2014: half were first in class, and rare cancers were the most frequent target. Health Aff. 2016;35:464–70. Scholar
  12. 12.
    Rodriguez-Monguio R, Spargo T, Seoane-Vazquez E. Ethical imperatives of timely access to orphan drugs: is possible to reconcile economic incentives and patients’ health needs? Orphanet J Rare Dis. 2017;12:1. Scholar
  13. 13.
    Onakpoya IJ, Spencer EA, Thompson MJ, Heneghan CJ. Effectiveness, safety and costs of orphan drugs: an evidence-based review. BMJ Open. 2015;5:e007199. Scholar
  14. 14.
    Chow SC, Wang J, Endrenyi L, Lachenbruch PA. Scientific considerations for assessing biosimilar products. Stat Med. 2013;32:370–81. Scholar
  15. 15.
    McKinnon R, Ward M. Safety considerations of biosimilars. Aust Prescr. 2016;39:188–9. Scholar
  16. 16.
    Stevenson JG. Clinical data and regulatory issues of biosimilar products. Am J Manag care. 2015;21(16 Suppl):s320–30.PubMedGoogle Scholar
  17. 17.
    Dylst P, Vulto A, Godman B, Simoens S. Generic medicines: solutions for a sustainable drug market? Appl Health Econ Health Policy. 2013;11:437–43. Scholar
  18. 18.
    Gammie T, Lu CY, Babar ZU. Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries. PLoS One. 2015;10:e0140002. Scholar
  19. 19.
    National Institute for Clinical Excellence (NICE). NICE Citizens Council Report: Ultra orphan drugs. 2004. Accessed 9 Sep 2017.
  20. 20.
    Hennekam RC. Care for patients with ultra-rare disorders. Eur J Med Genet. 2011;54:220–4. Scholar
  21. 21.
    Putzeist M, Mantel-Teeuwisse AK, Wied CC, Hoes AW, Leufkens HG, de Vrueh RL. Drug development for exceptionally rare metabolic diseases: challenging but not impossible. Orphanet J Rare Dis. 2013;8:179. Scholar
  22. 22.
    Braun MM, Farag-El-Massah S, Xu K, Cote TR. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nature Rev Drug Discov. 2010;9:519–22. Scholar
  23. 23.
    Harari S. Why we should care about ultra-rare disease. Eur Respir Rev. 2016;25:101–3. Scholar
  24. 24.
    Heemstra HE, van Weely S, Buller HA, Leufkens HG, de Vrueh RL. Translation of rare disease research into orphan drug development: disease matters. Drug Discov Today. 2009;14:1166–73. Scholar
  25. 25.
    Khan SA, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, et al. Epidemiology of mucopolysaccharidoses. Mol Genet Metab. 2017;121:227–40. Scholar
  26. 26.
    Leadley RM, Lang S, Misso K, Bekkering T, Ross J, Akiyama T, et al. A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases. Orphanet J Rare Dis. 2014;9:173. Scholar
  27. 27.
    Melnikova I. Rare diseases and orphan drugs. Nature Rev Drug Discov. 2012;11:267–8. Scholar
  28. 28.
    European Organisation for Rare Diseases (EURORDIS). Rare diseases: Understanding this public health priority. 2005. Accessed 9 Sep 2017.
  29. 29.
    Mancuso M, Orsucci D, Filosto M, Simoncini C, Siciliano G. Drugs and mitochondrial diseases: 40 queries and answers. Expert Opin Pharmacother. 2012;13:527–43. Scholar
  30. 30.
    Finsterer J, Frank M. Gastrointestinal manifestations of mitochondrial disorders: a systematic review. Therap Adv Gastroenterol. 2017;10:142–54. Scholar
  31. 31.
    Maser C, Toset A, Roman S. Gastrointestinal manifestations of endocrine disease. World J Gastroenterol. 2006;12:3174–9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pelentsov LJ, Fielder AL, Laws TA, Esterman AJ. The supportive care needs of parents with a child with a rare disease: results of an online survey. BMC Fam Pract. 2016;17:88. Scholar
  33. 33.
    Siddiq S, Wilson BJ, Graham ID, Lamoureux M, Khangura SD, Tingley K, et al. Experiences of caregivers of children with inherited metabolic diseases: a qualitative study. Orphanet J Rare Dis. 2016;11:168. Scholar
  34. 34.
    Thorat C, Xu K, Freeman SN, Bonnel RA, Joseph F, Phillips MI, et al. What the Orphan Drug Act has done lately for children with rare diseases: a 10-year analysis. Pediatrics. 2012;129:516–21. Scholar
  35. 35.
  36. 36.
    Franco P. Orphan drugs: the regulatory environment. Drug Discov Today. 2013;18:163–72. Scholar
  37. 37.
    97th United States Congress. Orphan Drug Act of 1983: Public Law 97-414—January 4, 1983. Accessed 9 Sep 2017.
  38. 38.
    98th United States Congress. Health Promotion and Disease Prevention Amendments of 1984: Public Law 98-551— October 30, 1984.–Pg2815.pdf. Accessed 9 Sep 017.
  39. 39.
    European Parliament and of the Council. Regulation (EC) No. 141/2000 on orphan medicinal products—16 December 1999. Accessed 9 Sep 17.
  40. 40.
    Clarke JT, Coyle D, Evans G, Martin J, Winquist E. Toward a functional definition of a “rare disease” for regulatory authorities and funding agencies. Value Health. 2014;17:757–61. Scholar
  41. 41.
    Hughes DA, Tunnage B, Yeo ST. Drugs for exceptionally rare diseases: do they deserve special status for funding? QJM. 2005;98:829–36. Scholar
  42. 42.
    European Organisation for Rare Diseases (EURORDIS). Medicines for children: better, more and faster. Eurordis position paper on the proposal for a regulation on medicinal products for paediatric use. 2005. Accessed 9 Sep 2017.
  43. 43.
    European Organisation for Rare Diseases (EURORDIS). Paediatric drugs and rare diseases. Accessed 9 Sep 2017.
  44. 44.
    Bourgeois FT, Hwang TJ. The Pediatric Research Equity Act moves into adolescence. JAMA. 2017;317:259–60. Scholar
  45. 45.
    Connor E, Cure P. “Creating hope” and other incentives for drug development for children. Sci Transl Med. 2011;3:66cm1. Scholar
  46. 46.
    Dooms M. From promising molecules to orphan drugs: early clinical drug development. Intractable Rare Dis Res. 2017;6:29–34. Scholar
  47. 47.
    Hwang TJ, Bourgeois FT. New regulatory paradigms for innovative drugs to treat pediatric diseases. JAMA Pediatrics. 2014;168:879–80. Scholar
  48. 48.
    Annemans L, Ayme S, Le Cam Y, Facey K, Gunther P, Nicod E, et al. Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL). Orphanet J Rare Dis. 2017;12:50. Scholar
  49. 49.
    Drummond M, Towse A. Orphan drugs policies: a suitable case for treatment. Eur J Health Econ. 2014;15:335–40. Scholar
  50. 50.
    Feltmate K, Janiszewski PM, Gingerich S, Cloutier M. Delayed access to treatments for rare diseases: who’s to blame? Respirology. 2015;20:361–9. Scholar
  51. 51.
    Kanters TA, Steenhoek A, Hakkaart L. Orphan drugs expenditure in the Netherlands in the period 2006–2012. Orphanet J Rare Dis. 2014;9:154. Scholar
  52. 52.
    European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP) guideline on the investigation of bioequivalence (Doc. Ref: CPMP/EWP/QWP/1401/98 Rev. 1/Corr **). 2010. Accessed 9 Sep 2017.
  53. 53.
    US Food and Drug Administration (FDA). FDA Fact Sheet: What’s involved in reviewing and approving generic drug applications?. 2015. Accessed 9 Sep 2017.
  54. 54.
    Tsiftsoglou AS, Ruiz S, Schneider CK. Development and regulation of biosimilars: current status and future challenges. BioDrugs. 2013;27:203–11. Scholar
  55. 55.
    Scavone C, Rafaniello C, Berrino L, Rossi F, Capuano A. Strengths, weaknesses and future challenges of biosimilars’ development. An opinion on how to improve the knowledge and use of biosimilars in clinical practice. Pharmacol Res. 2017;126:138–42. Scholar
  56. 56.
    Joppi R, Bertele V, Garattini S. Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU. Eur J Clin Pharmacol. 2013;69:1009–24. Scholar
  57. 57.
    Kanters TA, de Sonneville-Koedoot C, Redekop WK, Hakkaart L. Systematic review of available evidence on 11 high-priced inpatient orphan drugs. Orphanet J Rare Dis. 2013;8:124. Scholar
  58. 58.
    Cattaneo D, Andreoni M, Carosi G, Cauda R, Lazzarin A, Rizzardini G. Generic antiretrovirals for the treatment of HIV: a novel challenge for Western countries? Int J Clin Pharmacol Ther. 2017;55:381–93. Scholar
  59. 59.
    de Barros CM, Papoila AL. Therapeutic profile of orphan medicines. Pharmacoepidemiol Drug Saf. 2007;16:435–40. Scholar
  60. 60.
    Sherwin C. Issues associated with generic drugs used in children. GDUFA Regulatory Science Initiatives Public Meeting May 20th 2016. 2016. Accessed 9 Sep 2017.
  61. 61.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. New Engl J Med. 2003;349:1157–67. Scholar
  62. 62.
    Genazzani AA, Pattarino F. Difficulties in the production of identical drug products from a pharmaceutical technology viewpoint. Drugs R D. 2008;9:65–72.CrossRefPubMedGoogle Scholar
  63. 63.
    Verbeeck RK, Kanfer I, Walker RB. Generic substitution: the use of medicinal products containing different salts and implications for safety and efficacy. Eur J Pharm Sci. 2006;28:1–6. Scholar
  64. 64.
    Yu LX, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann DJ, et al. Novel bioequivalence approach for narrow therapeutic index drugs. Clin Pharmacol Ther. 2015;97:286–91. Scholar
  65. 65.
    Pai MP, Allen SE, Amsden GW. Altered steady state pharmacokinetics of levofloxacin in adult cystic fibrosis patients receiving calcium carbonate. J Cyst Fibros. 2006;5:153–7. Scholar
  66. 66.
    Woodcock J, Khan M, Yu LX. Withdrawal of generic budeprion for nonbioequivalence. N Engl J Med. 2012;367:2463–5. Scholar
  67. 67.
    Carswell JM, Gordon JH, Popovsky E, Hale A, Brown RS. Generic and brand-name l-thyroxine are not bioequivalent for children with severe congenital hypothyroidism. J Clin Endocrinol Metab. 2013;98:610–7. Scholar
  68. 68.
    Riva N, Guido PC, Ibanez J, Licciardone N, Rousseau M, Mato G, et al. Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin. Int J Clin Pharm. 2014;36:779–86. Scholar
  69. 69.
    Singh AK, Narsipur SS. Cyclosporine: a commentary on brand versus generic formulation exchange. J Transplant. 2011;2011:480642. Scholar
  70. 70.
    Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med. 2016;37:389–403. Scholar
  71. 71.
    Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet. 2001;40:573–85. Scholar
  72. 72.
    Duong SQ, Lal AK, Joshi R, Feingold B, Venkataramanan R. Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients. Pediatr Transplant. 2015;19:911–7. Scholar
  73. 73.
    Gonzalez F, Lopez R, Arriagada E, Carrasco R, Gallardo N, Lorca E. Switching stable kidney transplant recipients to a generic tacrolimus is feasible and safe, but it must be monitored. J Transpl. 2017;2017:5646858. Scholar
  74. 74.
    Molnar AO, Fergusson D, Tsampalieros AK, Bennett A, Fergusson N, Ramsay T, et al. Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ. 2015;350:h3163. Scholar
  75. 75.
    Ejerskov C, Krogh K, Ostergaard JR, Joensson I, Haagerup A. Gastrointestinal symptoms in children and adolescents with neurofibromatosis type 1. J Pediatr Gastroenterol Nutr. 2017. Scholar
  76. 76.
    Becker C, Bray-French K, Drewe J. Pharmacokinetic evaluation of idebenone. Expert Opin Drug Metab Toxicol. 2010;6:1437–44. Scholar
  77. 77.
    Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagreze WA, et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37:371–81. Scholar
  78. 78.
    Lyseng-Williamson KA. Idebenone: a review in Leber’s hereditary optic neuropathy. Drugs. 2016;76:805–13. Scholar
  79. 79.
    European Medicines Agency (EMA). Committee for Orphan Medicinal Products. Public summary of opinion on orphan designation: Imatinib mesilate for treatment of chronic myeloid leukaemia (4 February 2015; EMA/COMP/10370/2003 Rev.5). 2015. Accessed 9 Sep 2017.
  80. 80.
    Conti RM, Padula WV, Larson RA. Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU. Ann Hematol. 2015;94(Suppl 2):S249–57. Scholar
  81. 81.
    de Lemos ML, Kyritsis V. Clinical efficacy of generic imatinib. J Oncol Pharm Pract. 2015;21:76–9. Scholar
  82. 82.
    Yang YT, Nagai S, Chen BK, Qureshi ZP, Lebby AA, Kessler S, et al. Generic oncology drugs: are they all safe? Lancet Oncol. 2016;17:e493–501. Scholar
  83. 83.
    Jelkmann W. Biosimilar epoetins and other “follow-on” biologics: update on the European experiences. Am J Hematol. 2010;85:771–80. Scholar
  84. 84.
    Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, Jootar S, Intragumtornchai T, Tungsanga K, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int. 2011;80:88–92. Scholar
  85. 85.
    Tamilvanan S, Raja NL, Sa B, Basu SK. Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body. J Drug Target. 2010;18:489–98. Scholar
  86. 86.
    Rademacher TW, Parekh RB, Dwek RA. Glycobiology. Annu Rev Biochem. 1988;57:785–838. Scholar
  87. 87.
    Rush RS, Derby PL, Smith DM, Merry C, Rogers G, Rohde MF, et al. Microheterogeneity of erythropoietin carbohydrate structure. Anal Chem. 1995;67:1442–52.CrossRefPubMedGoogle Scholar
  88. 88.
    Schellekens H. The first biosimilar epoetin: but how similar is it? Clin J Am Soc Nephrol. 2008;3:174–8. Scholar
  89. 89.
    Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411–9. Scholar
  90. 90.
    Oh-eda M, Hasegawa M, Hattori K, Kuboniwa H, Kojima T, Orita T, et al. O-linked sugar chain of human granulocyte colony-stimulating factor protects it against polymerization and denaturation allowing it to retain its biological activity. J Biol Chem. 1990;265:11432–5.PubMedGoogle Scholar
  91. 91.
    Roberts AG, Johnston EV, Shieh JH, Sondey JP, Hendrickson RC, Moore MA, et al. Fully synthetic granulocyte colony-stimulating factor enabled by isonitrile-mediated coupling of large, side-chain-unprotected peptides. J Am Chem Soc. 2015;137:13167–75. Scholar
  92. 92.
    Declerck PJ, Darendeliler F, Goth M, Kolouskova S, Micle I, Noordam C, et al. Biosimilars: controversies as illustrated by rhGH. Curr Med Res Opin. 2010;26:1219–29. Scholar
  93. 93.
    Lee H. Is extrapolation of the safety and efficacy data in one indication to another appropriate for biosimilars? AAPS J. 2014;16:22–6. Scholar
  94. 94.
    Maro JC, Brown JS, Dal Pan GJ, Li L. Orphan therapies: making best use of postmarket data. J Gen Intern Med. 2014;29(Suppl 3):S745–51. Scholar
  95. 95.
    Meier T, Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009;256(Suppl 1):25–30. Scholar
  96. 96.
    Saltonstall PL, National Organization for Rare Disorders (NORD). Thoughtful biosimilars policy is best way to ensure optimum patient outcomes. 2014. Accessed 9 Sep 2017.
  97. 97.
    Menon D, Stafinski T, Dunn A, Wong-Rieger D. Developing a patient-directed policy framework for managing orphan and ultra-orphan drugs throughout their lifecycle. Patient. 2015;8:103–17. Scholar
  98. 98.
    European Organisation for Rare Diseases (EURORDIS). Breaking the access deadlock to leave no one behind: a reflection paper by EURORDIS and its members. 2017. Available from Accessed 9 Sep 2017.
  99. 99.
    Commission of the European Communities. Commission staff working document on the experience acquired as a result of the application of Regulation (EC) No 141/2000 on orphan medicinal products and account of the public health benefits obtained. Document on the basis of Article 10 of Regulation (EC) No 141/2000 (SEC [2006] 832). 2006. Accessed 9 Sep 2017.
  100. 100.
    Divino V, DeKoven M, Kleinrock M, Wade RL, Kim T, Kaura S. Pharmaceutical expenditure on drugs for rare diseases in Canada: a historical (2007–13) and prospective (2014–18) MIDAS sales data analysis. Orphanet J Rare Dis. 2016;11:68. Scholar
  101. 101.
    Hutchings A, Schey C, Dutton R, Achana F, Antonov K. Estimating the budget impact of orphan drugs in Sweden and France 2013–2020. Orphanet J Rare Dis. 2014;9:22. Scholar
  102. 102.
    Logviss K, Krievins D, Purvina S. Impact of orphan drugs on Latvian budget. Orphanet J Rare Dis. 2016;11:59. Scholar
  103. 103.
    Schey C, Milanova T, Hutchings A. Estimating the budget impact of orphan medicines in Europe: 2010–2020. Orphanet J Rare Dis. 2011;6:62. Scholar
  104. 104.
    Karpman D, Hoglund P. Orphan drug policies and use in pediatric nephrology. Pediatr Nephrol. 2017;32:1–6. Scholar
  105. 105.
    Dohle S, Siegrist M. Cognitive and affective determinants of generic drug acceptance and use: cross-sectional and experimental findings. Health Psychol Behav Med. 2013;1:5–14. Scholar
  106. 106.
    Rathe JO. The effect of generic switching on concerns about medicine and non-persistence among Danish adults in a general practice setting. Dan Med J. 2015;62:B5148.PubMedGoogle Scholar
  107. 107.
    Weissenfeld J, Stock S, Lungen M, Gerber A. The nocebo effect: a reason for patients’ non-adherence to generic substitution? Pharmazie. 2010;65:451–6.PubMedGoogle Scholar
  108. 108.
    Pisciotta L, Tozzi G, Travaglini L, Taurisano R, Lucchi T, Indolfi G, et al. Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. Atherosclerosis. 2017;265:124–32. Scholar
  109. 109.
    Paulino TL, Rafael MN, Hix S, Shigueoka DC, Ajzen SA, Kochi C, et al. Is age a risk factor for liver disease and metabolic alterations in ataxia Telangiectasia patients? Orphanet J Rare Dis. 2017;12:136. Scholar
  110. 110.
    El-Beshlawy A, Tylki-Szymanska A, Vellodi A, Belmatoug N, Grabowski GA, Kolodny EH, et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. Mol Genet Metab. 2017;120:47–56. Scholar
  111. 111.
    Charrow J, Esplin JA, Gribble TJ, Kaplan P, Kolodny EH, Pastores GM, et al. Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med. 1998;158:1754–60.CrossRefPubMedGoogle Scholar
  112. 112.
    Bi Y, Might M, Vankayalapati H, Kuberan B. Repurposing of proton pump inhibitors as first identified small molecule inhibitors of endo-beta-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease. Bioorg Med Chem Lett. 2017;27:2962–6. Scholar
  113. 113.
    Lichtman SM, Boparai MK. Anticancer drug therapy in the older cancer patient: pharmacology and polypharmacy. Curr Treat Options Oncol. 2008;9:191–203. Scholar
  114. 114.
    Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3:53–72. Scholar

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Authors and Affiliations

  1. 1.Section of Pharmacology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly

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