Paul Healy (1), Marco Marano (2), Marcello Montibeller (2), Bianca Maria Goffredo (2), Giuseppe Pontrelli (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics Group, University College London, London, UK (2) Ospedale Pediatrico Bambino Gesù (OPBG), Rome, Italy
Objectives: Sedation and analgesia are necessary components of the treatment of patients admitted to paediatric intensive care (PICU). In clinical practice, benzodiazepines are used in PICU due to their excellent efficacy profile and low toxicity. Lorazepam is a benzodiazepine with an intermediate duration of activity and has the advantage of not producing active metabolites.
Analgosedation is a sedative-minimizing technique; prioritizing pain control and analgesia, and consequently saving sedative agents for rescue therapy only [1]. While lorazepam itself represents a valid therapeutic option, its formulations contain propylene glycol, which can accumulate in tissues, leading to toxicity. To date, doses and dosing regimens for lorazepam remain off-label and there has been no pharmacokinetic studies in this setting. A model-based approach was used to design a prospective clinical study and optimize the dosing regimen of lorazepam for analgosedation, taking into account propylene glycol exposure and the potential risk of renal toxicity. Here we describe the population pharmacokinetics of both moieties in ventilated paediatric patients admitted to PICU.
Methods: Pharmacokinetic data from a pilot protocol in 6 paediatric patients (age range: 0.89–4.85 years) receiving varying doses of lorazepam (0.1-0.2 mg/kg) either as bolus (20 minutes) or continuous infusions (up to 72 hours) were used for the purposes of this investigation. Blood samples for the characterization of the concentrations of lorazepam and propylene glycol were collected as part of the therapeutic drug monitoring protocol before the bolus (time 0) and after the start of the continuous infusion and at varying time points between 10 minutes and 84 hr (an average of 6 samples per patient for both drugs)[ODP1] . Pharmacokinetic modelling was performed using prior distributions and model structure from a previously published model for lorazepam [2] and of propylene glycol [3]. For lorazepam, body weight was identified as the only significant covariate on clearance and volume. For propylene glycol, body weight was identified as a significant covariate on clearance and volume of distribution.
Results: A two-compartment pharmacokinetic model with allometric scaled parameters was used to describe the disposition of lorazepam, with clearance and volume estimates of 0.0763 L/h/kg (IIV 0.159 %CV) and 0.878 L/kg (IIV 0.216 %CV), respectively. For propylene glycol, plasma exposure was characterized by a one compartment model. Population estimates for clearance was 0.0916 L/h/kg, while volume of distribution was found to be 0.807 L/kg. As patients’ PK variability was greater than previously reported, a factor explaining explain this difference could be mechanical ventilation undergone by the participants.
Conclusions: This is the first time the pharmacokinetics of lorazepam and propylene glycol has been characterized for analgosedation in paediatric patients. Our analysis also shows the importance of Bayesian concepts for the analysis of sparse data, specially when additional blood sampling collection is not feasible or unethical. Whilst the off-label doses seem to be associated with acceptable analgosedation, our analysis indicate that alternative regimens may be required to ensure paediatric patients are exposed to acceptable levels of propylene glycol.
References:
[1] Devabhakthuni, S., Armahizer, M. J., Dasta, J. F., & Kane-Gill, S. L. (2012). Analgosedation: A Paradigm Shift in Intensive Care Unit Sedation Practice. Annals of Pharmacotherapy, 46(4), 530–540.
[2] Gonzalez, D et al. Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. Clin Pharmacokinet. 56:941–951 (2017).
[3] Jahn, A., Bodreau, C., Farthing, K. et al. Assessing Propylene Glycol Toxicity in Alcohol Withdrawal Patients Receiving Intravenous Benzodiazepines: A One-Compartment Pharmacokinetic Model. Eur J Drug Metab Pharmacokinet 43, 423–430 (2018).
[4] Ativan (lorazepam) injection, USP. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018140s041s042lbl.pdf [5] EMA/CHMP/704195/2013. https://www.ema.europa.eu/en/documents/report/propylene-glycol-used-excipient-report-published-support-questions-answers-propylene-glycol-used_en.pdf
Reference: PAGE () Abstr 9456 [www.page-meeting.org/?abstract=9456]
Poster: Drug/Disease Modelling - Paediatrics