Популяционная фармакокинетика меропенема у недоношенных новорожденных

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.Обоснование. Меропенем, антибиотик группы карбапенемов широкого спектра, часто применяется для лечения новорожденных, несмотря на наличие весьма ограниченных данных о фармакокинетике в этой популяции. Из-за фармакокинетических и фармакодинамических различий, а также вследствие значительных изменений, связанных с ростом и созреванием органов и систем организма, прямое масштабирование и экстраполяция режимов дозирования, рекомендованных взрослым или детям старшего возраста, с коррекцией на массу тела пациента могут приводить к высокому риску токсичности или отсутствию эффекта терапии. Цель исследования изучение фармакокинетики меропенема у недоношенных новорожденных на основе данных терапевтического лекарственного мониторинга в реальной клинической практике. Методы. Из 53 включенных в фармакокинетический/фармакодинамический анализ недоношенных новорожденных у 39 (73,6%) гестационный возраст был в пределах 2330 нед. Популяционные и индивидуальные значения фармакокинетических параметров были оценены с помощью программы NPAG из пакета Pmetrics на основе данных терапевтического лекарственного мониторинга (стратегия пикспад). Измерения концентрации проводились методом высокоэффективной жидкостной хроматографии. Однокамерная фармакокинетическая модель с процессом нулевого порядка поступления препарата в камеру и процессом элиминации первого порядка использовалась для описания фармакокинетических данных и расчета фармакодинамического параметра (%T МПК свободного препарата) для виртуальных пациентов, у которых моделировалось быстрое, среднее и медленное выведение меропенема при получении различных режимов дозирования для различных уровней минимальной подавляющей концентрации (МПК). Одно-и многофакторный регрессионный анализ применялся для выявления характеристик (ковариат) пациента (гестационный возраст, постнатальный возраст, постконцептуальный возраст, масса тела, клиренс креатинина, рассчитанный по формуле Шварца, и др.), влияющих на оцененные фармакокинетические параметры меропенема. Результаты. Идентифицированные популяционные фармакокинетические параметры меропенема у недоношенных новорожденных (период полувыведения T1/2 = 1,93 0,341 ч; клиренс CL = 0,26 0,085 л/ч/кг; объем распределения V = 0,71 0,22 л/ч) хорошо согласуются с опубликованными в литературе для взрослых, новорожденных и детей старшего возраста. Фармакокинетическое/фармакодинамическое моделирование показало, что режим дозирования 90 мг/кг/сут с интервалом введения 8 ч и 3-часовой инфузией в большинстве случаев имеет высокую вероятность достижения фармакодинамической цели при терапии основных внутрибольничных инфекций, даже для резистентных возбудителей с МПК 8 мг/л и выше. Заключение. Новорожденным и особенно недоношенным новорожденным свойственна значительная фармакокинетическая вариабельность. Дозирование меропенема недоношенным новорожденным на основе популяционной фармакокинетической/фармакодинамической модели может частично учесть эту вариабельность, но полностью объяснить ее с помощью ковариат не представляется возможным. Персонализация терапии на основе байесовского подхода и данных терапевтического лекарственного мониторинга пациента может помочь в достижении выбранной фармакодинамической цели

Population pharmacokinetic analysis of levetiracetam therapeutic drug monitoring data of preterm newborns with neonatal seizures

Neonatal seizures remain a significant neurologic condition with higher incidences in preterm newborns. There still is a lack of evidence-based recommendations for the optimal choice of antiseizure drug (ASD) and effective dosing in term and preterm neonates. Phenobarbital continues to be widely used as the first-line ASD in neonates. Levetiracetam (LEV) is a relatively new ASD with favorable safety profile and positive efficacy outcomes for neonatal seizures. LEV is increasingly being used to treat seizures in newborns. Objective of the research: the population PK modeling based on TDM data assessed at intravenous (IV) LEV monotherapy as the first-line ASD in preterm newborns. Materials and methods: of 45 preterm neonates included in the LEV retrospective PK analysis, gestational age (GA) ranged from 22 to 36 weeks, in 30 (67%) patients GA was 22-28 weeks. Population and individual PK parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough TDM. Samples were assayed by high-performance liquid chromatography. One-compartment PK model with zero-order input and first-order elimination was used to fit LEV concentration data from 101 TDM occasions (201 measured concentrations totally). In the majority of cases, the LEV daily doses were 30 mg/kg/day (ranged from 20 up to 50 mg/kg/day), administered twice a day with 12-hour dosing interval in divided doses. Univariate and multivariate regression analysis was used to evaluate the influence of patient’s covariates on distribution of the estimated LEV PK parameters. Results: when compared to adults and older children, preterm newborns were found to have in average a higher volume of distribution (V), longer half-life (T1/2) and lower clearance (CL). Taking into consideration the lower GA and PCA of the neonates included into this PK study, the identified population PK parameters of LEV in preterm newborns were in good agreement with those published in the literature for neonates: the estimated T1/2 values have a 20% to 80% range of 11 to 32 hrs, the median values for CL and V were 1,22 ml/min/kg and 1,5 L/kg, respectively. LEV was tolerated well in the study age-group, no serious adverse events were evident during or after 30-min IV LEV infusions. Conclusion: the study revealed significant variability in the estimated PK parameters in preterm infants. The results of regression analysis showed that it is not possible to fully explain PK variability using covariates in a statistical model. Personalizing of the LEV anti-seizure treatment for the preterm newborns can be based on the Bayesian forecasting approach and a patient’s TDM data. © 2021, Pediatria Ltd.. All rights reserved

Population pharmacokinetics of meropenem in preterm infants [Популяционная фармакокинетика меропенема у недоношенных новорожденных]

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patient's weight can result in increased risk of toxicity or treatment failures. Aims - to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T > MIC of free drug) for virtual “patients” with simulated fast, moderate and slow meropenem elimination “received” different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patient's covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 ± 0.341 h; clearance CL = 0.26 ± 0.085 L/h/kg; volume of distribution V = 0.71 ± 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC ≥ 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patient's therapeutic drug monitoring data can help to achieve desired pharmacodynamic target. © 2021 Izdatel'stvo Meditsina. All rights reserved

Особенности терапевтического лекарственного мониторинга леветирацетама у новорожденных

Neonatal seizures in fullterm and preterm infants represent a common neurological syndrome. Levetiracetam (LEV) is one of the new and widely prescribed secondor thirdline antiepileptic drug for the treatment of seizures. Routine therapeutic drug monitoring of LEV was not recommended due to its almost ideal pharmacokinetic profile: linear pharmacokinetics, predictable doseconcentration relationship, wide therapeutic index, favourable safety profile, and unlikely clinically significant drugdrug pharmacokinetic interactions. In newborns, drug pharmacokinetics may be under the influence of maturation process. LEV pharmacokinetics in newborns appears to be age (gestational, postnatal) dependent and highly variable within the age ranges. These aspects make therapeutic drug monitoring a useful procedure for therapy optimization in this specific patient population. In population modeling based on therapeutic drug monitoring and nonlinear mixed effects models, covariates were found that should significantly affect the LEV clearance and volume of distribution in newborns - creatinine clearance and total body weight. Using of these regression equations can help to adjust the LEV doses without the patient's measured concentration data. But the significant magnitudes of the interindividual variability remaining in these final regression models justify the need for therapeutic drug monitoring and Bayesian adaptive control for personalization of LEV dosage regimens in neonates.Неонатальные судороги у доношенных и недоношенных новорожденных (НР) являются часто встречающимся неврологическим синдромом. Одним из новых и широко назначаемых противоэпилептических препаратов 2-3й линии для терапии судорог у НР является леветирацетам (LEV). Рутинное применение терапевтического лекарственного мониторинга LEV не было рекомендовано, поскольку препарат имеет практически идеальный фармакокинетический профиль: линейная фармакокинетика, предсказуемое соотношение доза-концентрация, высокий терапевтический индекс, благоприятный профиль безопасности, маловероятное клинически значимое фармакокинетическое взаимовлияние с другими препаратами. У НР практически все основные процессы, определяющие фармакокинетику препарата, могут находиться под влиянием еще незаконченного процесса созревания. Фармакокинетика LEV у НР зависит от возраста (гестационного, постнатального), но внутри возрастных диапазонов наблюдается значительная межиндивидуальная вариабельность. Все это свидетельствует о необходимости терапевтического лекарственного мониторинга для оптимизации терапии LEV в этой специфической популяции пациентов. При популяционном моделировании с использованием данных терапевтического лекарственного мониторинга и нелинейных моделей смешанных эффектов были выявлены ковариаты, значимо влияющие на клиренс и объем распределения LEV у НР, - клиренс креатинина и масса тела. Использование таких регрессионных соотношений может помочь в корректировке доз LEV без измерения концентраций у пациента. Однако значительная доля межиндивидуальной вариабельности, которую не удается объяснить с помощью регрессионной модели, свидетельствует в пользу терапевтического лекарственного мониторинга и Байесовского адаптивного подхода для персонализации режимов дозирования LEV у НР

Фармакокинетика антибактериальных препаратов при муковисцидозе в детском возрасте

Cystic fibrosis (CF) is one of the most frequent hereditary multisystem disease. Pathogenesis of lung damage includes development of chronic microbial-inflammatory process on the background of severe violation of mucociliary clearance. Proper and timely antibiotic therapy of infectious process determines the disease prognosis greatly. To select an effective antibacterial drugs dosing regimen, it is necessary to take into account pathophysiological features of cystic fibrosis, which determine the unique pharmacokinetics (PK) in this category of patients. The review describes significant effect of age on such PK processes as: absorption, distribution, biotransformation, and elimination. The influence of factors affecting pharmacokinetics of antibacterial drugs in cystic fibrosis in childhood (transit through digestive tube, state of biliary system, biotransformation processes, etc.) is disclosed. Studying pharmacokinetics of antibacterial drugs in children with CF will increase the effectiveness of treatment, reduce the risks of antibiotic resistance, and improve the overall prognosis.Муковисцидоз (МВ) является одним из самых частых наследственных мультисистемных заболеваний. В патогенезе повреждения легких лежит развитие хронического микробно-воспалительного процесса на фоне грубого нарушения мукоцилиарного клиренса. Адекватная и своевременная антибактериальная терапия инфекционного процесса во многом определяет прогноз заболевания. Для выбора эффективного режима дозирования антибактериальных препаратов необходимо учитывать патофизиологические особенности муковисцидоза, которые обуславливают уникальность фармакокинетики (ФК) у этой категории пациентов. В обзоре описано значимое влияние возраста на ФК процессы, такие как: абсорбция, распределение, биотрансформация и элиминация. Раскрыто влияние факторов, влияющих на фармакокинетику антибактериальных препаратов при муковисцидозе в детском возрасте (транзит по пищеварительной трубке, состояние билиарной системы, процессы биотрансформации и т. д.). Изучение фармакокинетики антибактериальных препаратов у детей, больных МВ, позволит повысить эффективность проводимого лечения, снизить риски антибиотикорезистентности и в целом улучшить прогноз

Safety, pharmacokinetics and pharmacodynamics of an original glycoprotein IIb/IIIa inhibitor in healthy volunteers: results of the clinical trial [Результаты клинического исследования безопасности, фармакокинетики и фармакодинамики оригинального антитромбоцитарного препарата из группы ингибиторов гликопротеиновых IIb/IIIa-рецепторов у здоровых добровольцев]

Aim. To study the tolerability, safety, pharmacokinetics (PK) and pharmacodynamics of single intravenous infusions of Angipur in healthy male volunteers. Material and methods. The Phase I trial included 20 healthy male volunteers (mean age, 30,8±7,7 years; mean body weight, 77,4±12,1 kg). Angipur (0,02% concentrate for solution for infusion) was administered to every subject in single doses 0,015, 0,05, 0,09 mg/kg for 3 consecutive days. Volunteers were divided in 6 groups (1, 1, 3, 5, 5, 5); every following group was recruited only after the previous one finished the study. The following were assessed: rate and severity of adverse events (AEs), key PK parameters of Angipur and its antiplatelet activity by impedance aggregometry. Results. No moderate or severe AEs, as well as no serious AEs were reported according to obtained data of clinical and laboratory monitoring of healthy subjects. Totally 6 mild AEs were registered in 4 subjects. Four AEs (mild hematological deviations and episode of nose bleed) were classified as possibly related to study drug and 1 AE (positive fecal occult blood test) — probably related. Key PK parameters of Angipur in single intravenous doses 0,015, 0,05 и 0,09 mg/kg were determined as follows: Cmax — 12,44±4,689, 46,10±14,295, 92,48±33,896 ng/ml; Vd — 304,01±55,300, 299,67±64,244, 252,96±47,790 l; T1/2 — 6,72±1,290, 6,84±2,341, 6,06±2,287 h; Cl — 32,19±6,919, 32,29±8,357, 31,55±10,113 l/h, respectively. Dose proportionality (linear PK) for parameters Cmax, AUC0-t and AUC0-∞ was established. Dose-dependent reduction of ADP-induced platelet aggregation degree and area under curve was revealed at period of 15 min to 2-4 h after Angipur infusion in doses 0,05 and 0,09 mg/kg. Conclusion. Results of phase I clinical trial demonstrated good tolerability of single intravenous infusions of Angipur (0,015, 0,05 и 0,09 mg/kg) in healthy subjects. We determined key PK parameters and indicated dose-dependent antiplatelet activity of Angipur. © 2022 Vserossiiskoe Obshchestvo Kardiologov. All rights reserved

Age peculiarities of pharmacotherapy with amoxicillin preparations in children with cystic fibrosis

Amoxicillin and amoxicillin/clavulanate are the medicines of choice for the treatment of infections caused by Staphylococcus aureus and Haemophilus influenzae in children with cystic fibrosis (CF) n the Russian Federation. However, pharmacokinetics (PK) of amoxicillin for CF in childhood was never studied. Objective of the research: To study the pharmacokinetic parameters of amoxicillin in different age periods in children with CF. Materials and methods: 19 patients with CF aged from 2 to 16 years took part in the study. After taking the medicine in mean dose of 31,25 mg/kg (from 28 to 34,5 mg/kg), blood was taken every 1,5 hours after a single dose for 7,5 hours. Pharmacokinetic parameters were assessed using the non-compartmental method in three age subgroups: 2-5 years, 6-11 years, and 12-16 years. Results: High interindividual variability of studied PK parameters was revealed. The lowest values of median AUC0-t, μg*h/ml and AUC0-t norm (μg*h/ml)/(mg/kg) (11,34 and 0,4, respectively) were in the subgroup of children aged 2-5 years. The highest values of median AUC0-t, μg*h/ml and AUC0-t norm (μg*h/ml)/(mg/kg) (18,45 and 0,64, respectively) were in the subgroup of 12-16 years old adolescents with CF. Values of Cmax (μg/ml) and Cmax norm (μg/ml)/(mg/kg) in the younger age group median were 2,79 μg/ml and 0,1 (μg/ml)/(mg/kg), in adolescent subgroup-5,47 μg/ml and 0,16 (μg/ml)/(mg/kg), respectively. Median time to reach maximum amoxicillin concentration in blood plasma in the subgroup of children aged 2-5 years with CF was 1,5 hours (1,5-3 hours); in subgroups of 6-11 years and 12-16 years, the median was estimated as 3 hours. Conclusion: Considering the results obtained, it can be assumed that, on average, the total clearance of amoxicillin decreases with age. Further studies of PC/pharmacodynamics are needed to develop adequate dosing regimens of amoxicillin for CF, especially in the group of children under 5 years of age. © 2019, Pediatria Ltd.. All rights reserved