vspВопросы современной педиатрииCurrent Pediatrics1682-55271682-5535Издательство «ПедиатрЪ»10.15690/vsp.v17i4.1931vsp-1935Research ArticleМНЕНИЕ ПО ПРОБЛЕМЕEXPERT OPINIONПроблемы дозирования лекарственных средств у детей: известные факты и нерешенные вопросыDosage Problems in Children: Well-Known Facts and Unresolved Issueshttps://orcid.org/0000-0001-9292-4769МихайловаО. А.MikhailovaOlga A.https://orcid.org/0000-0002-0535-2916ДроздовВ. Н.DrozdovVladimir N.https://orcid.org/0000-0001-6528-1585ЛазареваН. Б.LazarevaNatalia В.

Лазарева Наталья Борисовна, доктор медицинских наук, профессор кафедры клинической фармакологии и пропедевтики внутренних болезней

119991, Москва, ул. Большая Пироговская, д. 2

natalia.lazareva@gmail.comhttps://orcid.org/0000-0001-6589-7654ШихЕ. В.ShikhEvgeniya V.Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияSechenov First Moscow State Medical University (Sechenov University)Russian Federation201805102018174350355Copyright © Михайлова О.А., Дроздов В.Н., Лазарева Н.Б., Ших Е.В., 20182018Михайлова О.А., Дроздов В.Н., Лазарева Н.Б., Ших Е.В.Mikhailova O.A., Drozdov V.N., Lazareva N.В., Shikh E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vsp.spr-journal.ru/jour/article/view/1935

Проблема дозирования лекарственных препаратов в детском возрасте обусловлена спецификой метаболизма лекарственных средств (ЛС) в организме ребенка. Клинических исследований по изучению физиологических особенностей в различные периоды детства и систематизированных данных на сегодняшний день недостаточно. По-прежнему актуально понимание характерных отличий, влияющих на биодоступность, распределение и экскрецию ЛС, особенно у детей старше 1 мес жизни. Результаты таких исследований необходимы для формирования рекомендаций по применению ЛС у детей с учетом их возраста и компенсации отсутствия данных прямых клинических исследований в педиатрии. Обсуждается возможность использования метода расчета дозы относительно содержания жировой ткани в организме в разные периоды детства и химических свойств вещества.

The problem of dosing drugs at an early age is conditioned by specific metabolism of medicinal products (MP) in the child's body. Currently, there are a few clinical trials on the study of physiological characteristics in different periods of childhood and systematised data. It is still relevant to understand the characteristic differences that affect the bioavailability, distribution and excretion of MP, especially in children over one month of life. The results of such studies are necessary in order to formulate the recommendations for use of MP in children taking into account their age and compensate for the lack of data from direct clinical trials in pediatrics. The possibility of using a dose calculation method regarding the fat content of the body in different periods of childhood and the chemical properties of the substance has been discussed.

детиклиническая фармакологиялекарственные средствадозированиеchildrenclinical pharmacologymedicinal productsdosageНе указанNot specifiedReferencesФедеральный закон Российской Федерации № ФЗ-61 от 12 апреля 2010 г. «Об обращении лекарственных средств». Доступно по: http://legalacts.ru/doc/federalnyi-zakon-ot-12042010-n-61fz-ob/ Ссылка активна на 12.07.2018.Federal Law of Russian Federation № 61-FZ «Ob obrashhenii lekarstvennyh sredstv» dated 2010 April 12. (In Russ). http://legalacts.ru/doc/federalnyi-zakon-ot-12042010-n-61fz-ob/Joseph DP, Caldwell PH, Craig JC. Registered pediatric clinical trials: a global context. Poster presentation at the International Congress of Pediatrics 2013 (ICP), the 27th Congress of International Pediatric Association; 2013 August 24–29; Melbourne, Australia.Joseph DP, Caldwell PH, Craig JC. Registered pediatric clinical trials: a global context. Poster presentation at the International Congress of Pediatrics 2013 (ICP), the 27th Congress of International Pediatric Association; 2013 August 24–29; Melbourne, Australia.Dunne J, Rodriguez WJ, Murphy D, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242–e1249. doi: 10.1542/peds.2010-3487.Dunne J, Rodriguez WJ, Murphy D, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242–e1249. doi: 10.1542/peds. 2010-3487.Saullo F, Saullo E, Caloiero M, et al. A questionnaire-based study in Calabria on the knowledge of off-label drugs in pediatrics. J Pharmacol Pharmacother. 2013;4(Suppl 1):S51–54. doi: 10.4103/0976-500X.120960.Saullo F, Saullo E, Caloiero M, et al. A questionnaire-based study in Calabria on the knowledge of off-label drugs in pediatrics. J Pharmacol Pharmacother. 2013;4(Suppl 1):S51–54. doi: 10.4103/0976-500X.120960.Мардганиева Э.А., Рябченко В.А., Малышева Е.В., и др. Оценка состояния проблемы нерегламентированных назначений в педиатрии: результаты опроса педиатров и родителей // Качественная клиническая практика. — 2016. — № 4 — С. 63–69.Mardganieva EA, Ryabchenko VA, Malysheva EV, et al. The problem of off label drug use in pediatrics: pediatricians and parents survey results. Kachestvennaya klinicheskaya praktika. 2016;(4):63–69. (In Russ).Smith MC, Williamson J, Yaster M, et al. Off-label use of medications in children undergoing sedation and anesthesia. Anesth Analg. 2012;115(5):1148–1154. doi: 10.1213/ANE.0b013e3182501b04.Smith MC, Williamson J, Yaster M, et al. Off-label use of medications in children undergoing sedation and anesthesia. Anesth Analg. 2012;115(5):1148–1154. doi: 10.1213/ANE.0b013e318 2501b04.Баранов А.А., Намазова-Баранова Л.С., Басаргина Е.Н., и др. Хроническая сердечная недостаточность у детей. Клинические рекомендации. — М.: ПедиатрЪ; 2016.Baranov AA, NamazovaBaranova LS, Basargina EN, et al. Khronicheskaya serdechnaya nedostatochnost’ u detei. Klinicheskie rekomendatsii. Moscow: Pediatr’’; 2016. (In Russ).Титова А.Р., Асецкая И.Л., Поливанов В.А., Зырянов С.К. Фар макоэпидемиологическое исследование безопасности применения лекарственных препаратов у детей на основе анализа российской базы спонтанных сообщений // Качественная кли ническая практика. — 2017. — № 3 — С. 43–52.Titova AR, Aset skaya IL, Polivanov VA, Zyryanov SK. Pharmacoepidemiological study of the safety of drug use in children by analyzing the Russian database of spontaneous reports. Kachestvennaya klinicheskaya praktika. 2017;(3):43–52. (In Russ).Ueno K, Tanaka K, Shiokawa M, Horiuchi Y. Age-dependent changes of renal excretion of theophylline in asthmatic children. Ann Pharmacother. 2016;28(2):281–282. doi: 10.1177/106002809402800225.Ueno K, Tanaka K, Shiokawa M, Horiuchi Y. Age-dependent changes of renal excretion of theophylline in asthmatic children. Ann Pharmacother. 2016;28(2):281–282. doi: 10.1177/106002809402800225.Zhou Q, Pan S-d, Zhu L-l, et al. Weight-based dosing in medication use: what should we know? Patient Prefer Adherence. 2016;10:549–560. doi: 10.2147/PPA.S103156.Zhou Q, Pan S-d, Zhu L-l, et al. Weight-based dosing in medication use: what should we know? Patient Prefer Adherence. 2016;10:549–560. doi: 10.2147/PPA.S103156.Food and Drug Administration, HHS. International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Fed Regist. 2000;65(242):78493–78494.Food and Drug Administration, HHS. International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Fed Regist. 2000;65(242):78493–78494.Matalova P, Urbanek K, Anzenbacher P. Specific features of pharmacokinetics in children. Drug Metab Rev. 2016;48(1):70–79. doi: 10.3109/03602532.2015.1135941.Matalova P, Urbanek K, Anzenbacher P. Specific features of pharmacokinetics in children. Drug Metab Rev. 2016;48(1):70–79. doi: 10.3109/03602532.2015.1135941.Smits A, Annaert P, Allegaert K. Drug disposition and clinical practice in neonates: cross talk between developmental physiology and pharmacology. Int J Pharm. 2013;452(1–2):8–13. doi: 10.1016/j.ijpharm.2012.03.035.Smits A, Annaert P, Allegaert K. Drug disposition and clinical practice in neonates: cross talk between developmental physiology and pharmacology. Int J Pharm. 2013;452(1–2):8–13. doi: 10.1016/j.ijpharm.2012.03.035.Shafiq N, Malhotra S, Gautam V, et al. Evaluation of evidence for pharmacokinetics-pharmacodynamics-based dose optimization of antimicrobials for treating Gram-negative infections in neonates. Indian J Med Res. 2017;145(3):299–316. doi: 10.4103/ijmr.IJMR_723_15.Shafiq N, Malhotra S, Gautam V, et al. Evaluation of evidence for pharmacokinetics-pharmacodynamics-based dose optimization of antimicrobials for treating Gram-negative infections in neonates. Indian J Med Res. 2017;145(3):299–316. doi: 10.4103/ijmr.IJMR_723_15.Anderson GD, Lynn AM. Optimizing pediatric dosing: a deve lopmental pharmacologic approach. Pharmacotherapy. 2009;29(6): 680–690. doi: 10.1592/phco.29.6.680.Anderson GD, Lynn AM. Optimizing pediatric dosing: a deve lopmental pharmacologic approach. Pharmacotherapy. 2009;29(6): 680–690. doi: 10.1592/phco.29.6.680.Pacifici GM. Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur J Clin Pharmacol. 2008;65(4):419–427. doi: 10.1007/s00228-008-0599-y.Pacifici GM. Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur J Clin Pharmacol. 2008;65(4):419–427. doi: 10.1007/s00228-008-0599-y.Latasch L, Freye E. [Pain and opioids in preterm and newborns. (In German).] Anaesthesist. 2002;51(4):272–284.Latasch L, Freye E. [Pain and opioids in preterm and newborns. (In German).] Anaesthesist. 2002;51(4):272–284.Клиническая фармакология. Учебник / Под ред. В.Г. Кукеса, Д.А. Сычева. 5-е изд., испр. и доп. — М.: ГЭОТАР-Медиа; 2015. — 1024 с.Klinicheskaya farmakologiya. Uchebnik. Ed by Kukes V.G., Sychev D.A. 5th ed. revised and updated. Moscow: GEOTAR-Media; 2015. 1024 p. (In Russ).Reed MD, Besunder JB. Developmental pharmacology: ontogenic basis of drug disposition. Pediatr Clin North Am. 1989;36(5): 1053–1074. doi: 10.1016/S0031-3955(16)36757-8.Reed MD, Besunder JB. Developmental pharmacology: ontogenic basis of drug disposition. Pediatr Clin North Am. 1989;36(5): 1053–1074. doi: 10.1016/S0031-3955(16)36757-8.de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999;36(6):439–452. doi: 10.2165/00003088-199936060-00005.de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999;36(6):439–452. doi: 10.2165/00003088-199936060-00005.Oesterheld JR. A review of developmental aspects of cytochrome P450. J Child Adolesc Psychopharmacol. 1998;8(3):161–174. doi: 10.1089/cap.1998.8.161.Oesterheld JR. A review of developmental aspects of cytochrome P450. J Child Adolesc Psychopharmacol. 1998;8(3):161–174. doi: 10.1089/cap.1998.8.161.Аткинсон А.Д., Абернети Д.Р., Дэниэлс Ч.И., и др. Принципы клинической фармакологии. Пер. с англ. / Под общ. ред. Г.Т. Сухих. — М.: Практическая медицина; 2013. — 530 с.Atkinson AD, Abernethy DR, Daniels Ch, et al, editors. Principles of clinical pharmacology. Translated from English. Ed by G.T. Sukhikh. Moscow: Prakticheskaya meditsina; 2013. 530 p. (In Russ).Лукьянова Е.М. Нефротоксичность антибиотиков у новорожденных // Педиатрическая фармакология. — 2003. — Т. 1. — № 4 — С. 33–41.Lukyanova EM. Antibiotic nephrotoxicity in neonates. Pediatric pharmacology. 2013;1(4):33–41. (In Russ).Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet. 1978;3(1):72–91. doi: 10.2165/00003088-197803010-00005.Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet. 1978;3(1):72–91. doi: 10.2165/ 00003088-197803010-00005.Eber E, Midulla F, editors. ERS Handbook of paediatric respiratory medicine. 1st ed. Sheffield, UK: European Respiratory Society; 2013. 719 p.Eber E, Midulla F, editors. ERS Handbook of paediatric respiratory medicine. 1st ed. Sheffield, UK: European Respiratory Society; 2013. 719 p.Chavasse R, Seddon P, Bara A, McKean M. Short acting beta2agonists for recurrent wheeze in children under two years of age. Cochrane Database Syst Rev. 2002;(3):CD002873. doi: 10.1002/14651858.CD002873.Chavasse R, Seddon P, Bara A, McKean M. Short acting beta2agonists for recurrent wheeze in children under two years of age. Cochrane Database Syst Rev. 2002;(3):CD002873. doi: 10.1002/14651858.CD002873.Laer S, Elshoff J-P, Meibohm B, et al. Development of a safe and effective pediatric dosing regimen for sotalol based on population pharmacokinetics and pharmacodynamics in children with supraventricular tachycardia. J Am Coll Cardiol. 2005;46(7): 1322–1330. doi: 10.1016/j.jacc.2005.06.061.Laer S, Elshoff J-P, Meibohm B, et al. Development of a safe and effective pediatric dosing regimen for sotalol based on population pharmacokinetics and pharmacodynamics in children with supraventricular tachycardia. J Am Coll Cardiol. 2005;46(7): 1322–1330. doi: 10.1016/j.jacc.2005.06.061.Cameron JL. Interrelationships between hormones, behavior, and affect during adolescence: understanding hormonal, physical, and brain changes occurring in association with pubertal activation of the reproductive axis. Introduction to part III. Ann N Y Acad Sci. 2004;1021(1):110–123. doi: 10.1196/annals.1308.012.Cameron JL. Interrelationships between hormones, behavior, and affect during adolescence: understanding hormonal, physical, and brain changes occurring in association with pubertal activation of the reproductive axis. Introduction to part III. Ann N Y Acad Sci. 2004;1021(1):110–123. doi: 10.1196/annals.1308.012.Kennedy MJ. Hormonal Hormonal regulation of hepatic drugmetabolizing enzyme activity during adolescence. Clin Pharmacol Ther. 2008;84(6):662–673. doi: 10.1038/clpt.2008.202.Kennedy MJ. Hormonal Hormonal regulation of hepatic drugmetabolizing enzyme activity during adolescence. Clin Pharmacol Ther. 2008;84(6):662–673. doi: 10.1038/clpt.2008.202.Donelli MG, Zucchetti M, Robatto A, et al. Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. Med Pediatr Oncol. 1995;24(3):154–159. doi: 10.1002/mpo.2950240303.Donelli MG, Zucchetti M, Robatto A, et al. Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. Med Pediatr Oncol. 1995;24(3):154–159. doi: 10.1002/mpo.2950240303.Mahmood I. Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings. Clin Pharmacokinet. 2014;53(4):327–346. doi: 10.1007/s40262-014-0134-5.Mahmood I. Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings. Clin Pharmacokinet. 2014;53(4):327–346. doi: 10.1007/s40262-014-0134-5.Mahmood I. Prediction of drug clearance in children: a review of different methodologies. Expert Opin Drug Metab Toxicol. 2015; 11(4):573–587. doi: 10.1517/17425255.2015.1019463.Mahmood I. Prediction of drug clearance in children: a review of different methodologies. Expert Opin Drug Metab Toxicol. 2015; 11(4):573–587. doi: 10.1517/17425255.2015.1019463.Edginton AN, Shah B, Sevestre M, Momper JD. The integration of allometry and virtual populations to predict clearance and clearance variability in pediatric populations over the age of 6 years. Clin Pharmacokinet. 2013;52(8):693–703. doi: 10.1007/s40262-0130065-6.Edginton AN, Shah B, Sevestre M, Momper JD. The integration of allometry and virtual populations to predict clearance and clearance variability in pediatric populations over the age of 6 years. Clin Pharmacokinet. 2013;52(8):693–703. doi: 10.1007/s40262-0130065-6.Xiong Y, Fukuda T, Knibbe CA, Vinks AA. Drug dosing in obese children: challenges and evidence-based strategies. Pediatr Clin North Am. 2017;64(6):1417–1438. doi: 10.1016/j.pcl.2017.08.011.Xiong Y, Fukuda T, Knibbe CA, Vinks AA. Drug dosing in obese children: challenges and evidence-based strategies. Pediatr Clin North Am. 2017;64(6):1417–1438. doi: 10.1016/j.pcl.2017.08.011.Strolin Benedetti M, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1(3):447–471. doi: 10.1517/17425255.1.3.447.Strolin Benedetti M, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1(3):447–471. doi: 10.1517/17425255.1.3.447.Harskamp-van Ginkel MW, Hill KD, Becker KC, et al. Drug dosing and pharmacokinetics in children with obesity: a systematic review. JAMA Pediatr. 2015;169(7):678–685. doi: 10.1001/ jamapediatrics.2015.132.Harskamp-van Ginkel MW, Hill KD, Becker KC, et al. Drug dosing and pharmacokinetics in children with obesity: a systematic review. JAMA Pediatr. 2015;169(7):678–685. doi: 10.1001/ jamapediatrics.2015.132.

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