Dataset Information

Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus.

ABSTRACT: BACKGROUND:Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. OBJECTIVE:Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. METHODS:From 19 children (median age 4.9 years [range 9 months-15.3 years], median weight 18 kg [range 7.8-70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients' clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. RESULTS:A two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. CONCLUSIONS:The pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma.

SUBMITTER: Vet NJ

PROVIDER: S-EPMC7007440 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus.

Vet Nienke J NJ de Winter Brenda C M BCM Koninckx Muriel M Boeschoten Shelley A SA Boehmer Annemie L M ALM Verhallen Jacintha T JT Plötz Frans B FB Vaessen-Verberne Anja A AA van der Nagel Bart C H BCH Knibbe Catherijne A J CAJ Buysse Corinne M P CMP de Wildt Saskia N SN Koch Birgit C P BCP de Hoog Matthijs M

Clinical pharmacokinetics 20200201 2

<h4>Background</h4>Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer.<h4>Objective</h4>Our aim was to develop a population pharmacokinetic model ...[more]

PMID: 31432470

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Project description:Objectives There is a paucity of data on the use of intravenous magnesium sulfate infusion in children with refractory status asthmaticus. The purpose of this study was to evaluate the efficacy and safety of prolonged magnesium sulfate infusion as an advanced therapy. Methods This is a single center retrospective study of children admitted to our pediatric intensive care unit (PICU) with status asthmaticus requiring continuous albuterol. Treatment group included patients receiving magnesium for ≥4 h and control group included those on other therapies only. Patients were matched 1:4 based on age, sex, obesity, pediatric index of mortality III and pediatric risk of mortality III scores. Primary outcomes included PICU length of stay (LOS) and mechanical ventilation (MV) requirement. Secondary outcomes included mortality, extracorporeal membrane oxygenation (ECMO) requirement, analyses of factors associated with PICU LOS and MV requirement and safety of magnesium infusion. Logistic and linear regressions were employed to determine factors associated with MV requirement and PICU LOS, respectively. Results Treatment and control groups included 27 and 108 patients, respectively. Median initial infusion rate was 15 mg/kg/hour, with median duration of 28 h. There was no difference in the MV requirement between the treatment and control groups [7 (25.9%) vs. 20 patients (18.5%), p = 0.39]. Median PICU LOS and ECMO use were significantly higher in treatment vs. control group [(3.63 vs. 1.09 days, p < 0.01) and (11.1 vs. 0%, p < 0.01), respectively]. No mortality difference was noted. On regression analysis, patients receiving ketamine and higher prednisone equivalent dosing had higher odds of MV requirement [OR 19.29 (95% CI 5.40–68.88), p < 0.01 and 1.099 (95% CI 1.03–1.17), p < 0.01, respectively]. Each mg/kg increase in prednisone equivalent dosing corresponded to an increase in PICU LOS by 0.13 days (95% CI 0.096–0.160, p < 0.01). Magnesium infusions were not associated with lower MV requirement or lower PICU LOS after controlling for covariates. Fourteen (51.9%) patients in the treatment group had an adverse event, hypotension being the most common. Conclusion Magnesium sulfate infusions were not associated with MV requirement, PICU LOS or mortality.

Project description:ObjectivesTo determine risk factors associated with admission to a PICU with or without endotracheal intubation for an asthma exacerbation. We hypothesized that children with critical and near-fatal asthma would have distinguishing clinical features but varying degrees of asthma severity and measures of type 2 inflammation.DesignRetrospective analysis of prospectively collected data of children with asthma recruited into outpatient asthma clinical research studies at Emory University between 2004 and 2015.SettingLarge, free-standing academic quaternary care children's hospital in Atlanta, GA.PatientsChildren 6-18 years old with physician-diagnosed and confirmed asthma.InterventionsNone.Measurements and main resultsA total of 579 children were analyzed with 170 children (29.4%) being admitted to the PICU for an asthma exacerbation in their lifetime. Of these 170 children with a history of critical asthma, 24.1% were classified as having mild-to-moderate asthma, and 83 of 170 children (48.8%) had been intubated and experienced near-fatal asthma. Multiple logistic regression was used to identify risk factors associated with increased odds of PICU admission with or without endotracheal intubation. Hospitalization within the prior 12 months of survey (odds ratio, 8.19; 95% CI, 4.83-13.89), a history of pneumonia (odds ratio, 2.56; 95% CI, 1.52-4.29), having a designation of increased chronic asthma severity on high-dose inhaled corticosteroids (odds ratio, 2.76; 95% CI, 1.62-4.70), having a father with asthma (odds ratio, 2.15; 95% CI, 1.23-3.76), living in a region with a higher burden of poverty (odds ratio, 1.28; 95% CI, 1.02-1.61), and being of black race (odds ratio, 2.01; 95% CI, 1.05-3.84) were all associated with increased odds of PICU admission with or without intubation.ConclusionsOur findings suggest that there are factors associated with critical and near-fatal asthma, distinct from the chronic asthma severity designations, that should be the focus of future investigation.

Project description:PurposeTo determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies.Patients and methodsSorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated.ResultsIn PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; P < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (P = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (P = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (P < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent (P = 0.0015) but not with sequential (P = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (P = 0.0004) and sorafenib N-oxide (P = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR.ConclusionsSorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.

Dataset Information

Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus.

Publications

Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus.

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