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. Nienke J. Vet and Brenda C. M. de Winter contributed equally to this work.In this prospective study, we developed a population pharmacokinetic model of intravenous R-and S-salbutamol in children with status asthmaticus admitted to the intensive care unit.The model described the data well and showed that a loading dose seems valid to reach higher initial R-salbutamol concentrations with a possible therapeutic advantage.This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol.

Efficacy of A Loading Dose of IV Salbutamol in Children With Severe Acute Asthma Admitted to A PICU: A Randomized Controlled Trial

“…The pharmacologic activity of salbutamol resides predominantly in the (R)-isomer, with little or no activity, and concerns about adverse reactions, attributed to the (S)-isomer [6,25]. Based on a previous population PK model of IV R-and S-salbutamol in SAA children, a loading dose seemed valid to reach higher initial Rsalbutamol concentrations with a possible therapeutic advantage [6].…”

“…In both groups continuous infusion of salbutamol was started at the same time or continued in children who already received salbutamol IV. The loading dose of 15 mcg/kg was based on international guidelines [5,7] and a previous pilot study into the PK of IV salbutamol in children [6].…”

“…A study by Starkey et al [9] summarized current evidence and gaps in knowledge and concluded that the PK-PD of IV salbutamol in children is probably similar, but data are limited. A previous pilot study [6] on the PK of IV salbutamol in children has yielded a model of IV R-and S-salbutamol that described the data well and showed that in children a loading dose should be considered. This model can be used to evaluate PK-PD relationship of IV salbutamol in children, and the effectiveness and tolerability of (a loading dose) IV salbutamol.…”

“…The elimination of (R)-salbutamol is much more rapid than that of (S)-salbutamol, which leads to relatively higher plasma concentrations of (S)-salbutamol. There are concerns that particularly high exposure to S-salbutamol may have negative effects [6]. However, very little is known about the pharmacokinetics (PK) and pharmacodynamics (PD) of IV salbutamol in children and the rationale behind current dosing strategies.…”

Finger-Prick Blood Sampling for Therapeutic Drug Monitoring: Be Aware of Skin Contamination by Nebulized Drugs

“…We recently performed a pharmacokinetic study in children receiving intravenously administered salbutamol for severe acute asthma. 2 During data analysis, we noticed 8 aberrantly high concentrations of salbutamol ( Fig. 1) that could not be attributed to the pharmacokinetic profile of the drug, drug administration errors, samples taken from the drug administration line, clinical symptoms, sample mix-ups, or other logistic errors.…”