Compounded drugs as an alternative to the therapeutical gaps of inborn errors of metabolism

Fachini, Adrielle da Silva; Malaquias, Lorena Freitas Barros; Nogueira, Luma de Lira; Giacone, Ludmila Alvim Gomes Pinho; Tavares, Noemia Urruth Leão; Cardoso, Maria Teresinha de Oliveira; Gelfuso, Guilherme Martins; Silva, Dayde Lane Mendonça da; Santana, Rafael Santos

doi:10.1590/s2175-97902023e21109

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Brasil

Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 59 • 2023 • https://doi.org/10.1590/s2175-97902023e21109 copy

Compounded drugs as an alternative to the therapeutical gaps of inborn errors of metabolism

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Inborn errors of metabolism are rare disorders with few therapeutic options for their treatments, which can make patients suffer with complications. Therefore, compounded drugs might be a promising option given that they have the ability of meeting the patient’s specific needs, (i) identification of the main drugs described in the literature; (ii) proposal of compounding systems and (iii) calculation of the budgetary addition for the inclusion of these drugs into the Brazilian Unified Health System. The research conducted a literature review and used management data as well as data obtained from official Federal District government websites. The study identified 31 drugs for the treatment of inborn errors of metabolism. Fifty eight percent (58%) (18) of the medicines had their current demand identified, which are currently unmet by the local Health System. The estimated budget for the production of compounded drugs was of R$363,16.98 per year for approximately 300 patients. This estimated cost represents a budgetary addition of only 0.17% from the total of expenditures planned for drug acquirement. There is a therapeutic gap for inborn errors of metabolism and compounding pharmacies show potential in ensuring access to medicine therapy with a low-cost investment.

Keywords:
Rare diseases; Metabolism; Inborn errors; Therapeutic gap; Compounded drugs

ITEM	DRUG	REFERENCE
Organic Acidurias	Riboflavin	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
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		Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
	Sodium Benzoate	Baumgartner et al., 2014Baumgartner, M.R. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014; 9(1), pp. 1-36. doi: 10.1186/s13023-014-0130-8. https://doi.org/10.1186/s13023-014-0130-...
	Biotin	Lilliu, 2010Lilliu, F. Treatment of organic acidurias and urea cycle disorders. Journal of Maternal-Fetal and Neonatal Medicine. 2010; 23 (SUPPL. 3), pp. 73-75. doi: 10.3109/14767058.2010.509932. https://doi.org/10.3109/14767058.2010.50...
	Sodium phenylbutyrate	Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
	Sodium phenylbutyrate	Lilliu, 2010Lilliu, F. Treatment of organic acidurias and urea cycle disorders. Journal of Maternal-Fetal and Neonatal Medicine. 2010; 23 (SUPPL. 3), pp. 73-75. doi: 10.3109/14767058.2010.509932. https://doi.org/10.3109/14767058.2010.50...
	Glycine	Alfadhel et al. 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
	Glycine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	Hydroxycobalamin	Baumgartner et al., 2014Baumgartner, M.R. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014; 9(1), pp. 1-36. doi: 10.1186/s13023-014-0130-8. https://doi.org/10.1186/s13023-014-0130-...
	L-Arginine	Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
	L-Arginine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	Lysine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	L-Carnitine	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
		Baumgartner et al., 2014Baumgartner, M.R. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014; 9(1), pp. 1-36. doi: 10.1186/s13023-014-0130-8. https://doi.org/10.1186/s13023-014-0130-...
		Kölker et al., 2011Kölker, S. et al. Diagnosis and management of glutaric aciduria type I - revised recommendations. Journal of Inherited Metabolic Disease. 2011; 34(3), pp. 677-694. doi: 10.1007/s10545-011-9289-5. https://doi.org/10.1007/s10545-011-9289-...
	L-Isoleucine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	L-Valina	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	N-carbamyl glutamate	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
		Baumgartner et al., 2014Baumgartner, M.R. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014; 9(1), pp. 1-36. doi: 10.1186/s13023-014-0130-8. https://doi.org/10.1186/s13023-014-0130-...
		Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
	Thiamine	Lilliu, 2010Lilliu, F. Treatment of organic acidurias and urea cycle disorders. Journal of Maternal-Fetal and Neonatal Medicine. 2010; 23 (SUPPL. 3), pp. 73-75. doi: 10.3109/14767058.2010.509932. https://doi.org/10.3109/14767058.2010.50...
Pyridoxine-dependent Seizures	Pyridoxal Phosphate	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
Pyridoxine-dependent Seizures	Pyridoxal Phosphate	Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
Biotinidase deficiency	Biotine	Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
Primary and Secondary Carnitine Deficiency	L-Carnitine	Lilliu, 2010Lilliu, F. Treatment of organic acidurias and urea cycle disorders. Journal of Maternal-Fetal and Neonatal Medicine. 2010; 23 (SUPPL. 3), pp. 73-75. doi: 10.3109/14767058.2010.509932. https://doi.org/10.3109/14767058.2010.50...
		Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
		Sutton et al., 2012Sutton, V.R. et al. Chronic management and health supervision of individuals with propionic acidemia. Molecular Genetics and Metabolism . 2012; 105(1), pp. 26-33. Available at: http://dx.doi.org/10.1016/j.ymgme.2011.08.034. http://dx.doi.org/10.1016/j.ymgme.2011.0...
Glutathione Synthetase Deficiency	Vitamin E	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
Primary Coenzyme Q10 deficiency	Ubiquinone (Coenzyme Q10)	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
Primary Coenzyme Q10 deficiency	Ubiquinone (Coenzyme Q10)	Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
Urea cycle disorders	Sodium Benzoate	Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
		Lilliu, 2010Lilliu, F. Treatment of organic acidurias and urea cycle disorders. Journal of Maternal-Fetal and Neonatal Medicine. 2010; 23 (SUPPL. 3), pp. 73-75. doi: 10.3109/14767058.2010.509932. https://doi.org/10.3109/14767058.2010.50...
		Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
	Biotin	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
		Baumgartner et al., 2014Baumgartner, M.R. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014; 9(1), pp. 1-36. doi: 10.1186/s13023-014-0130-8. https://doi.org/10.1186/s13023-014-0130-...
		Conitec, 2012Comissão Nacional de Incorporação de Tecnologias no SUS - CONITEC. Biotina para o Tratamento da Deficiência de Biotinidase. Relatório de Recomendação 06. 2012; pp 1-17.
	Sodium phenylbutyrate	Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
	L-Arginine	Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
	L-Arginine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	L-Citrulline	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
	L-Citrulline	Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
	Lysine	Kölker et al., 2011Kölker, S. et al. Diagnosis and management of glutaric aciduria type I - revised recommendations. Journal of Inherited Metabolic Disease. 2011; 34(3), pp. 677-694. doi: 10.1007/s10545-011-9289-5. https://doi.org/10.1007/s10545-011-9289-...
	N-carbamyl glutamate	Häberle et al., 2012Häberle, J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases . 2012; 42(6), pp. 1192-1230. doi: 10.1002/ jimd.12100. https://doi.org/10.1002/ jimd.12100....
	N-carbamyl glutamate	Schiff, Blom, 2012Schiff, M. and Blom, H.J. Treatment of inherited homocystinurias. Neuropediatrics. 2012; 43(6), pp. 295-304. doi: 10.1055/s-0032-1329883. https://doi.org/10.1055/s-0032-1329883....
	Pyridoxine	Schiff, Blom, 2012Schiff, M. and Blom, H.J. Treatment of inherited homocystinurias. Neuropediatrics. 2012; 43(6), pp. 295-304. doi: 10.1055/s-0032-1329883. https://doi.org/10.1055/s-0032-1329883....
	Pyridoxine	Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
	Thiamine	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
	Thiamine	Frazier et al., 2014Frazier, D.M. et al. Nutrition management guideline for maple syrup urine disease: An evidence- and consensus-based approach. Molecular Genetics and Metabolism . 2014; 112(3) pp. 210-217. Available at: http://dx.doi.org/10.1016/j.ymgme.2014.05.006. http://dx.doi.org/10.1016/j.ymgme.2014.0...
Maple Syrup Urine Disease	L-Isoleucine	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
	L-Isoleucine	Singh et al., 2016Singh, R.H. et al. Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach. Molecular Genetics and Metabolism . 2016; 118(2), pp. 72-83. doi: 10.1016/j.ymgme.2016.04.008. https://doi.org/10.1016/j.ymgme.2016.04....
	L-Valina	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
	L-Valina	Frazier et al., 2014Frazier, D.M. et al. Nutrition management guideline for maple syrup urine disease: An evidence- and consensus-based approach. Molecular Genetics and Metabolism . 2014; 112(3) pp. 210-217. Available at: http://dx.doi.org/10.1016/j.ymgme.2014.05.006. http://dx.doi.org/10.1016/j.ymgme.2014.0...
	Thiamine	Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
Phenylketonuria	Glutamine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....
	Sapropterina	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
		Cunningham et al., 2012Cunningham, A. et al. Recommendations for the use of sapropterin in phenylketonuria. Molecular Genetics and Metabolism. 2012; 106(3) pp. 269-276. Available at: http://dx.doi.org/10.1016/j.ymgme.2012.04.004. http://dx.doi.org/10.1016/j.ymgme.2012.0...
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Familial hypercholesterolemia	Atorvastatin	Vuorio et al., 2017Vuorio, A. et al. Statins for children with familial hypercholesterolemia. Cochrane Database of Systematic Reviews 2019(11). 2017. doi: 10.1002/14651858.CD006401. pub5. https://doi.org/10.1002/14651858.CD00640...
	Colesevelam	Davidson, 2011Davidson, M.H. A systematic review of bile acid sequestrant therapy in children with familial hypercholesterolemia. Journal of Clinical Lipidology. 2011; 5(2) pp. 76-81. Available at: http://dx.doi.org/10.1016/j.jacl.2011.01.005. http://dx.doi.org/10.1016/j.jacl.2011.01...
	Colestipol
	Cholestyramine
	Pravastatin	O’Gorman et al., 2009O’Gorman, C.S., Higgins, M.F. and O’Neill, M.B. Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: Evaluation of cholesterol changes and side effects. Pediatric Cardiology. 2009; 30(4), pp. 482-489. doi: 10.1007/s00246-008-9364-3. https://doi.org/10.1007/s00246-008-9364-...
	Pravastatin	Vuorio et al., 2017Vuorio, A. et al. Statins for children with familial hypercholesterolemia. Cochrane Database of Systematic Reviews 2019(11). 2017. doi: 10.1002/14651858.CD006401. pub5. https://doi.org/10.1002/14651858.CD00640...
	Rosuvastatin	Vuorio et al., 2017Vuorio, A. et al. Statins for children with familial hypercholesterolemia. Cochrane Database of Systematic Reviews 2019(11). 2017. doi: 10.1002/14651858.CD006401. pub5. https://doi.org/10.1002/14651858.CD00640...
	Simvastatin	O’Gorman et al., 2009O’Gorman, C.S., Higgins, M.F. and O’Neill, M.B. Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: Evaluation of cholesterol changes and side effects. Pediatric Cardiology. 2009; 30(4), pp. 482-489. doi: 10.1007/s00246-008-9364-3. https://doi.org/10.1007/s00246-008-9364-...
	Simvastatin	Vuorio et al., 2017Vuorio, A. et al. Statins for children with familial hypercholesterolemia. Cochrane Database of Systematic Reviews 2019(11). 2017. doi: 10.1002/14651858.CD006401. pub5. https://doi.org/10.1002/14651858.CD00640...
Homocystinuria	Folic Acid	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
	Betaine	Diekman et al., 2014Diekman, E.F., De Koning, T.J., Verhoeven-Duif, N.M., Rovers, M.M. and Van Hasselt, P.M. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurology. 2014; 71(2), pp. 188-194. doi: 10.1001/jamaneurol.2013.4915. https://doi.org/10.1001/jamaneurol.2013....
	Betaine	Morris et al., 2017Morris, A.A.M. et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. Journal of Inherited Metabolic Disease . 2017; 40(1), pp. 49-74. doi: 10.1007/s10545-016-9979-0. https://doi.org/10.1007/s10545-016-9979-...
	Hydroxycobalamin	Schiff, Blom, 2012Schiff, M. and Blom, H.J. Treatment of inherited homocystinurias. Neuropediatrics. 2012; 43(6), pp. 295-304. doi: 10.1055/s-0032-1329883. https://doi.org/10.1055/s-0032-1329883....
	Pyridoxine	Morris et al., 2017Morris, A.A.M. et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. Journal of Inherited Metabolic Disease . 2017; 40(1), pp. 49-74. doi: 10.1007/s10545-016-9979-0. https://doi.org/10.1007/s10545-016-9979-...
	Folinic Acid	Alfadhel et al., 2013Alfadhel M, Al-Thihli K, Moubayed H, Eyaid W, Al-Jeraisy M. Drug treatment of inborn errors of metabolism: a systematic review. Arch Dis Child. 2013;98(6):454-461.
		Schiff, Blom, 2012Schiff, M. and Blom, H.J. Treatment of inherited homocystinurias. Neuropediatrics. 2012; 43(6), pp. 295-304. doi: 10.1055/s-0032-1329883. https://doi.org/10.1055/s-0032-1329883....
		Schwartz, Souza, Giugliani, 2008Schwartz IV, Souza CFM, Giugliani R. Treatment of inborn errors of metabolism. J Pediatr. (Rio J). 2008;84(4 Sup):S8-S19.
Tyrosinemia Type 1	Phenylalanine	Van Vliet et al., 2014Van Vliet, D., Derks, T.G., Van Rijn, M., De Groot, M.J., Macdonald, A., Heiner-Fokkema, M.R. and Van Spronsen, F.J. Single amino acid supplementation in aminoacidopathies: A systematic review. Orphanet Journal of Rare Diseases . 2014; 9(1), pp. 1-14. doi: 10.1186/1750-1172-9-7. https://doi.org/10.1186/1750-1172-9-7....

ACTIVE INGREDIENT	DOSES
ACTIVE INGREDIENT	PAPERS	DYNAMED	MICROMEDEX
Folic Acid	5-30 mg/d	-	0,5-5mg/d
Folinic Acid	1-5 mg/d	-	-
	5-15 mg/d
	5-30 mg/d
Atorvastin	10-20 mg/d	10-20 mg/d	10-20 mg/d
Sodium Benzoate	150-250 mg/kg/d	-	-
Sodium Benzoate	200-300 mg/kg/d	-	-
Betain	150-250 mg/kg/d (in 2-3 doses)	-	100 mg/kg/d100 mg/kg/d (2 doses)
Betain	5-20 g (in 2-3 doses)	-	100 mg/kg/d100 mg/kg/d (2 doses)
Biotin	5-20 mg/d	1-10 mg/d	5-10 mg/d
Colesevelam	1,875 g or 3,75 g/d (2x) or (1x)	1,875 g or 3,75 g/d (2x) or (1x)	1,875 g or 3,75 g/d (2x) or (1x)
Colestipol	2-12 g/d	2 g/d (1-2x)	2 g/d (1-2x)
Cholestyramine	8 g/d	4 g (1 or 2x)	4 g (1 or 2x)
Phenylalanine	20-40 mg/kg/d	-	-
Sodium phenylbutyrate	500 mg/kg/d	-	450-600 mg/kg/d (in 3-6 doses)
Sodium phenylbutyrate	200-600 mg/kg/d	-	450-600 mg/kg/d (in 3-6 doses)
Glycine	150-300 mg (4 doses)	-	-
Glutamine	200-1000 mg/kg/d	-	-
Hydroxycobalamin	5-21 mg/week	-	400 mcg/d
L-Arginine	100-300 mg/kg/d	-	-
L-Carnitine	100-300 mg/kg/d (in 2-4 doses)	50-100 mg/kg/d (in 2-3 doses)	50 mg/kg/d (divided doses)
L-Citrulline	100-200 mg/kg/d	-	-
Lysine	50-100 mg/kg/d	-	-
L-Isoleucine	20-120 mg/kg/d	-	-
L-Valina	20-120 mg/kg/d	-	-
N-Carbamyl Glutamate	100-250 mg/kg/d (in 3-4 doses)	100-250 mg/kg/d (in 2-4 doses)	100-250 mg/kg/d (in 2-4 doses)
Pyridoxal Phosphate	30-50 mg/kg/d (in 4-6 doses)	-	-
Pyridoxine	10 mg/kg/d-500 mg/d(max)	-	-
Pravastatin	5, 10, 20 ou 40 mg/d	40 mg/d	20 ou 40 ou 80 mg/d
Riboflavin	100-150 mg/d (in 2-3 doses)	-	-
Rosuvastatin	5-20 mg/d	5-20 mg/d	20 mg/d
Sapropterina	5-20 mg/kg/d	10 mg/kg/d	10 mg/kg/d
Simvastatin	10-40 mg/d	10-40 mg/d	5-40 mg/d
Simvastatin	20 mg/d	10-40 mg/d	5-40 mg/d
Thiamine	10-1000 mg/d
Ubiquinone (Coenzyme Q₁₀)	2-15mg/kg/d (2x/day)
Vitamin E	10 mg/kg/d

N°	DRUG	STANDARD DOSAGE	PHARMACEUTICAL PRODUCT TO BE DEVELOPED FOR CHILDREN
1	Folic Acid	5mg/d	Oral solution 5mg/mL (30mL)
2	Folinic Acid	10mg/d	Oral solution 10mg/mL (100mL)
3	Atorvastin	10mg/d	Oral solution 10mg/mL (100mL)
4	Sodium Benzoate	200mg/kg/d	Oral solution 250mg/mL (100mL)
5	Betain	100mg/kg/d (in 2 doses)	Oral solution 250mg/mL (120mL)
6	Biotin	10mg/d	Solution 10mg/mL (60mL)
7	Colesevelam	1,875g/d (2x/d)	Oral solution 1,875g/mL (60mL)
8	Colestipol	2g/d (60mL) (1-2x/d)	Oral solution 2g/mL
9	Cholestyramine	4g/d (1-2x/d)	Oral solution 4g/mL (60mL)
10	Phenylalanine	20mg/kg/d	Oral solution 100mg/mL (100mL ou 200mL)
11	Sodium phenylbutyrate	450mg/kg/d (in 3-6 doses)	Oral solution 450mg/mL (150mL)
12	Glycine	200mg/kg/d (in 4 doses)	Solution 250mg/mL (120mL)
13	Glutamine	200mg/kg/d	Oral solution 250mg/mL (100mL)
14	Hydroxycobalamin	400mcg/d	Oral solution 400mcg/mL (30 mL)
15	L-Arginine	100mg/kg/d	Solution 500mg/mL (100mL)
16	L-Carnitine	100mg/kg/d (in 2-4 doses)	Oral solution 125mg/mL (100mL)
17	L-Citrulline	100mg/kg/d	Solution 500mg/mL (100mL)
18	Lysine	50mg/kg/d	Oral solution 250mg/mL (100mL)
19	L-Isoleucine	50mg/kg/d	Solution 250mg/mL (100mL)
20	L-Valina	50mg/kg/d	Oral solution 250mg/mL (100mL)
21	N-Carbamyl Glutamate	100mg/kg/d (em 2-4 doses)	Solution 125mg/mL (120mL)
22	Pyridoxal Phosphate	40mg/kg/d (in 4-6 doses)	Oral solution 50mg/mL (120mL)
23	Pyridoxine	10mg/kg/d	Oral solution 50mg/mL (100mL)
24	Pravastatin	10mg/d	Oral solution 10mg/mL (100mL)
25	2Riboflavin	200mg/d (in 2-3 doses)	Solution 100mg/mL (100mL)
26	Rosuvastatin	20mg/d	Oral solution 20mg/mL (100mL)
27	Sapropterina	10mg/kg/d	Oral solution 50mg/mL (100mL)
28	Simvastatin	20mg/d	Oral solution 20mg/mL (30mL)
29	Thiamine	200mg/d	Oral solution 200mg/mL (120mL)
30	Ubiquinone (Coenzyme Q₁₀)	5mg/kg/d (2x/d)	Oral solution 25mg/mL (100mL)
31	Vitamin E	10mg/kg/d	Oral solution 50mg/mL (100mL)

Nº	DRUG	ESTIMATED MONTHLY PRESCRIPTIONS (N°)	ESTIMATED MONTHLY COST (BRL$)	ESTIMATED ANNUAL COST (BRL$)
1	Folic Acid oral solution 5mg/mL (30mL)	20	976.14	11,713.68
2	Folinic Acid oral solution 10mg/mL (100mL)	05	661.35	7,936.20
3	Sodium benzoate oral solution 250mg/mL (100mL)	30	2,941.20	35,294.40
4	Betaine oral solution 250mg/mL (120mL)	10	1,547.00	18,564.00
5	Biotin solution 10mg/mL (60mL)	30	1,568.25	18,819.00
6	Glycine solution 250mg/mL (120mL)	10	814.45	9,773.40
7	Glutamine oral solution 250mg/mL (100mL)	10	839.20	10,070.40
8	Hydroxycobalamin oral solution 400mcg/mL (30 mL)	50	3,888.00	46,656.00
9	L-arginine solution 500mg/mL (100mL)	15	1,255.50	15,066.00
10	L-carnitine oral solution 125mg/mL (100mL)	50	4,361.00	52,332.00
11	L-isoleucine solution 250mg/mL (100mL)	05	418.50	5,022.00
12	L-valine oral solution 250mg/mL (100mL)	05	412.13	4,945.50
13	Pyridoxal phosphate oral solution 50mg/mL (120mL)	10	1,244.50	14,934.00
14	Pyridoxine oral solution 50mg/mL (100mL)	30	2,815.50	33,786.00
15	Riboflavin solution 100mg/mL (100mL)	30	2,596.50	31,158.00
16	Thiamine solution 200mg/mL (120mL)	30	2,911.80	34,941.60
17	Ubiquinone (Coenzyme Q₁₀) oral solution 25mg/mL (100mL)	10	616.20	7,394.40
18	Vitamin E oral solution 50mg/mL (100mL)	10	459.20	5,510.40
TOTAL		360	BRL$ 30.326,42	BRL$ 363.916,98

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: R. S. Santana. Universidade de Brasília-Campus Universitário Darcy Ribeiro, s/n, Asa Norte, Brasília, DF, 70910-900. Phone: (61) 98132-3520. E-mail: rafael.santana@unb.br