Shan Pan (1), Yucheng Sheng (1,2), Frank Kloprogge (1), Brian J. Anderson (3), Padmanabhan Ramnarayan (4), Sandra Walsh (4), Joseph F. Standing (1)
(1) UCL Institute of Child Health, London, United Kingdom, (2) Sanofi-Aventis, Clinical Pharmacology Translational Medicine, Shanghai, China, (3) University of Auckland, Auckland, New Zealand, (4) Great Ormond Street Hospital, London, United Kingdom
Objectives: Salbutamol is a short-acting selective beta-2 adrenoceptor agonist for treating asthma in adults and children. Intravenous salbutamol (IVS) is routinely used as second line treatment for childhood acute severe asthma as per the British Thoracic Society (BTS). IVS doses in children are extrapolated from adults based on body weight, and no maximum dose in children has been recommended while children may receive doses far greater than the maximum adult dose. Our study aimed to develop new rational dosing guidelines for IVS in children through exploring relationships between IVS blood concentrations and efficacy and toxicity measurements in children with acute severe asthma.
Methods: A prospective Phase II study was conducted in Emergency Departments (EDs) and Paediatric Intensive Care Units (PICUs) across London, UK (EudraCT No. 2014-002996-27). Children with acute severe asthma were recruited from two distinct cohorts: the ED cohort and the Children’s Acute Transport Service (CATS) cohort. In the latter case, children were taken to PICUs.
Plasma concentrations, efficacy and toxicity measurements were available from children receiving IVS with intermittent nebulised doses. Asthma severity was measured by the three-item composite score Paediatric Asthma Severity Score (PASS) [1]. Toxicity-associated physiological measurements were collected from blood gas, blood glucose and cardiovascular tests. In total eight individual toxicity measures were examined in the current study.
One- and two-compartment PK models were tested for the time course of salbutamol plasma concentrations after IVS. Plasma concentrations at baseline were estimated due to long and uncertain pre-treatment history of salbutamol. PASS (re-categorised into three) and the individual items (each with three categories) were assessed by ordered logistic regression considering time-varying plasma concentrations. For toxicity measures, a hypothetical effect compartment was added to examine whether delayed onset in toxicity effects occurred after IVS.
Correlation analysis was conducted between predicted plasma concentrations and observed toxicity measurements, and between predicted and observed toxicity measurements.
Data manipulation and graphical analysis were conducted in R (version 3.4.3). IVS PKPD model development was performed in NONMEM® (version 7.3).
Results: In the current study, data were available from 47 children aged between 1 and 15, with 165 plasma samples, 102 PASS measurements, and 178-245 measurements for each toxicity measure.
A one-compartment PK model well described the time course of salbutamol plasma concentrations after nebulised and intravenous salbutamol doses. Body weight, added allometrically, was found as a statistically significant covariate. The covariate effect of age was not found significant through maturation function.
For PASS and the individual items, the addition of linear concentration-efficacy relationship didn’t significantly reduce objective function value (OBJV), except for work of breathing. Emax concentration-efficacy relationship, however, significantly reduced OBJV based on likelihood ratio test or Akaike information criterion (AIC), with reported EC50 values ranging between 0.2 ng/mL and 0.5 ng/mL.
Correlations between plasma concentrations and toxicity measurements were not found significant, and sigmoidal Emax concentration-toxicity relationships significantly improved the correlation coefficient for all. Toxic effects increased immediately with the increase of plasma concentrations, the opposite for pH and base excess measures; these findings were consistent with physiological observations. EC50 values were estimated between 28 ng/mL and 360 ng/mL.
Conclusions: The current study explored PKPD relationships for efficacy and toxicity measurements after IVS. Based on the PKPD relationships, future investigation concerning clinically significant changes is required to determine maximum IVS dose in children with acute severe asthma.
References:
[1] Gorelick et al. Acad Emerg Med. 2004;11(1):10-18
Reference: PAGE 27 (2018) Abstr 8710 [www.page-meeting.org/?abstract=8710]
Poster: Drug/Disease Modelling - Paediatrics