pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2026-14-4-362-376pmedpharm-1921Research ArticleОРИГИНАЛЬНАЯ СТАТЬЯRESEARCH ARTICLEВзаимосвязь фармакогенетики и фармакокинетики CFTR-модуляторов в популяции детей с муковисцидозомThe relationship between the pharmacogenetics and pharmacokinetics of CFTR modulators in a population of children with cystic fibrosishttps://orcid.org/0000-0002-6348-6867ЗыряновС. К.ZyryanovS. K.

доктор медицинских наук, профессор, заведующий кафедрой общей и клинической фармакологии ФГАОУ ВО РУДН; врач-клинический фармаколог ГБУЗ ГКБ № 24 ДЗ г. Москвы. 

1. Россия, 117198, г. Москва, ул. Миклухо-Маклая, д.6.

2. Россия, 127015, г. Москва, ул. Писцовая, д.10.

Doctor of Sciences (Medicine), Professor, Head of the Department of General and Clinical Pharmacology, People’s Friendship University (RUDN University); clinical pharmacologist of City Clinical Hospital No. 24. 

1. 6 Miklukho-Maklaya Str., Moscow, Russia, 117198.

2. 10 Pistsovaya Str., Moscow, Russia, 127015.

zyryanov_sk@rudn.universityhttps://orcid.org/0000-0001-6395-0407КондратьеваЕ. И.KondratyevaE. I.

доктор медицинских наук, профессор, руководитель научно-клинического отдела муковисцидоза, заведующая кафедрой генетики болезней дыхательной системы ФГБУН «Медико-генетический научный центр имени академика Н.П. Бочкова»; заместитель директора по научной работе ГБУЗ МО «НИКИ детства Минздрава Московской области». 

1. Россия, 115522, Москва, ул. Москворечье, д.1.

2. Россия, 141009, г. Мытищи, ул. Коминтерна, д.24а, стр.1.

Doctor of Sciences (Medicine), Professor, Head of the Research and Clinical Department of Cystic Fibrosis, Head of the Department of Genetics of Respiratory Diseases, Research Centre for Medical Genetics; Deputy Director for Research, Childhood Research Institute of the Ministry of Health of the Moscow Region.

1. 1 Moskvorechye StR., Moscow, Russia, 115522.

2. 24a Komintern Str., Bldg. 1, Mytishchi, Russia, 141009.

elenafpk@mail.ruhttps://orcid.org/0000-0001-5013-3360ЖекайтеЕ. К.ZhekaiteE. K.

кандидат медицинских наук, ведущий научный сотрудник научно-клинического отдела муковисцидоза, доцент кафедры генетики болезней дыхательной системы ФГБУН «Медико-генетический научный центр имени академика Н.П. Бочкова»; ведущий научный сотрудник отдела наследственных и метаболических болезней, врач-педиатр отделения муковисцидоза ГБУЗ МО «НИКИ детства Минздрава Московской области». 

1. Россия, 115522, Москва, ул. Москворечье, д.1.

2. Россия, 141009, г. Мытищи, ул. Коминтерна, д.24а, стр.1.

Candidate of Sciences (Medicine), Leading Researcher of the Research and Clinical Department of Cystic Fibrosis, Assistant Professor of the Department of Genetics of Respiratory Diseases, Research Centre for Medical Genetics; Leading Researcher of the Department of Hereditary and Metabolic Diseases, Pediatrician, Cystic Fibrosis Unit, Childhood Research Institute. 

1. 1 Moskvorechye StR., Moscow, Russia, 115522.

2. 24a Komintern Str., Bldg. 1, Mytishchi, Russia, 141009.

Elena_zhekayte@mail.ruhttps://orcid.org/0000-0001-7729-2169БутрановаО. И.ButranovaO. I.

кандидат медицинских наук, доцент кафедры общей и клинической фармакологии Медицинского института ФГАОУ ВО РУДН. 

Россия, 117198, г. Москва, ул. Миклухо-Маклая, д.6.

Candidate of Sciences (Medicine), Assistant Professor of the Department of General and Clinical Pharmacology of the Institute of Medicine, Peoples' Friendship University (RUDN University). 

6 Miklukho-Maklaya Str., Moscow, Russia, 117198.

butranova-oi@rudn.ruhttps://orcid.org/0000-0001-8555-5969БочковП. О.BochkovP. O.

кандидат медицинских наук, заместитель директора по научной работе ГБУЗ МНПЦЛИ ДЗМ. 

Россия, 115580, г. Москва, Ореховый б-р, д.49, к.1.

Candidate of Sciences (Medicine), Deputy Director for Research of the Moscow Scientific and Practical Center for Laboratory Studies.

49/1 Orekhovy Blvd., Moscow, Russia, 1115580.

bok-of@yandex.ru1. Федеральное государственное автономное образовательное учреждение высшего образования «Российский университет дружбы народов имени Патриса Лумумбы». 2. Государственное бюджетное учреждение города Москвы «Городская клиническая больница № 24 Департамента здравоохранения города Москвы».Россия1. Peoples' Friendship University (RUDN University). 2. City Clinical Hospital No. 24.Russian Federation1. Федеральное государственное бюджетное научное учреждение «Медико-генетический научный центр имени академика Н.П. Бочкова». 2. Государственное бюджетное учреждение здравоохранения Московской области «Научно-исследовательский клинический институт детства министерства здравоохранения Московской области».Россия1. Research Centre for Medical Genetics. 2. Childhood Research Institute.Russian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Российский университет дружбы народов имени Патриса Лумумбы».РоссияPeoples' Friendship University (RUDN University).Russian FederationГосударственное бюджетное учреждение здравоохранения города Москвы «Московский научно-практический центр лабораторных исследований Департамента здравоохранения города Москвы».РоссияMoscow Scientific and Practical Center for Laboratory Research.Russian Federation202620072026144362376Copyright © Зырянов С.К., Кондратьева Е.И., Жекайте Е.К., Бутранова О.И., Бочков П.О., 20262026Зырянов С.К., Кондратьева Е.И., Жекайте Е.К., Бутранова О.И., Бочков П.О.Zyryanov S.K., Kondratyeva E.I., Zhekaite E.K., Butranova O.I., Bochkov P.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/1921

Тройная комбинация элексакафтор/тезакафтор/ивакафтор является одним из ключевых инструментов таргетной фармакотерапии муковисцидоза. В педиатрической популяции ее применение может сопровождаться вариабельным терапевтическим ответом, в основе чего могут лежать возрастные особенности фармакокинетики, а также влияние генетического полиморфизма ферментов биотрансформации.

Цель

Цель. Проанализировать фармакокинетические параметры элексакафтора, тезакафтора ивакафтора и лумакафтора у пациентов с муковисцидозом, а также изучить влияние различных полиморфизмов генов цитохромов Р450 (CYP2С6*4, CYP2С19*2, CYP2D6*4) и гена UGT1A1 на фармакокинетику.

Материалы и методы

Материалы и методы. В проспективное одноцентровое исследование включено 32 пациента с муковисцидозом в возрасте от 6 до 18 лет, из них 29 получали комбинацию элексакафтор/тезакафтор/ивакафтор, 3 — двойную комбинацию ивакафтор/лумакафтор. Концентрации аналитов в плазме определяли методом ВЭЖХ-МС/МС в пяти временных точках в течение 12 ч после приёма препаратов. Молекулярно-генетический анализ проводили на тотальной ДНК, выделенной из лейкоцитов цельной крови с помощью метода фенол-хлороформной экстракции.

Результаты

Результаты. Выявлена значительная межиндивидуальная вариабельность фармакокинетических параметров всех изученных CFTR-модуляторов. Нормированные максимальные концентрации элексакафтора и ивакафтора были значительно выше у пациентов в возрасте ≥12 лет (p=0,027 и p=0,046 соответственно). Носительство генотипа CYP2C9*4 (GG), ассоциированного с медленным метаболизмом, приводило к статистически значимому повышению системной экспозиции элексакафтора (p=0,007) и ивакафтора (p=0,034). Для генотипа CYP2D6*4 (AA) выявлено значимое повышение концентрации элексакафтора через 3 ч после приёма (p=0,041). Полиморфизм гена UGT1A1, включая генотипы, ассоциированные с синдромом Жильбера, не оказывал значимого влияния на суммарную экспозицию изученных препаратов, при этом отмечены более низкие концентрации тезакафтора и элексакафтора в отдельных точках у носителей аллеля *28.

Заключение

Заключение. Фармакокинетика CFTR-модуляторов у детей характеризуется высокой вариабельностью и зависит от возраста и полиморфизма генов, кодирующих изоферменты CYP2C9 и CYP2D6. Полученные данные обосновывают необходимость дальнейших исследований для оптимизации дозирования с учетом генетических и демографических факторов.

The triple combination of elexacaftor / tezacaftor / ivacaftor is one of the key tools for targeted pharmacotherapy of cystic fibrosis. In the pediatric population, its use may be accompanied by a variable therapeutic response, which may be due to age-related pharmacokinetic features, as well as the influence of genetic polymorphism of biotransformation enzymes.

The aim

The aim. To analyze the pharmacokinetic parameters of elexacaftor, tezacaftor, ivacaftor, and lumacaftor in patients with cystic fibrosis, and to study the influence of various polymorphisms of cytochrome P450 genes (CYP2C6*4, CYP2C19*2, CYP2D6*4) and the UGT1A1 gene on pharmacokinetics.

Materials and Methods

Materials and Methods. The prospective single-center study included 32 patients with cystic fibrosis aged 6 to 18 years, of whom 29 received the combination of elexacaftor / tezacaftor / ivacaftor, and 3 received the dual combination of ivacaftor / lumacaftor. Analyte concentrations in plasma were determined by HPLC-MS/MS at five time points within 12 hours after drug administration. Molecular genetic analysis was performed on total DNA isolated from whole blood leukocytes using the phenol-chloroform extraction method.Results. Significant inter-individual variability in the pharmacokinetic parameters of all studied CFTR modulators was revealed. Normalized maximum concentrations of elexacaftor and ivacaftor were significantly higher in patients aged ≥ 12 years (p = 0.027 and p = 0.046, respectively). Carriage of the CYP2C9*4 (GG) genotype, associated with slow metabolism, led to a statistically significant increase in the systemic exposure of elexacaftor (p = 0.007) and ivacaftor (p = 0.034). For the CYP2D6*4 (AA) genotype, a significant increase in elexacaftor concentration 3 hours after administration was found (p = 0.041). Polymorphism of the UGT1A1 gene, including genotypes associated with Gilbert’s syndrome, did not have a significant effect on the total exposure of the studied drugs, while lower concentrations of tezacaftor and elexacaftor were noted at individual time points in carriers of the *28 allele.

Conclusion

Conclusion. The pharmacokinetics of CFTR modulators in children are characterized by high variability and depend on age and the polymorphism of genes encoding CYP2C9 and CYP2D6 isoenzymes. The obtained data justify the need for further research to optimize dosing, taking into account genetic and demographic factors.

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