Chenyao Liu (1), Alessandro Di Deo (1), Martina Franzin (2), Marianna Lucafò (3), Egidio Barbi (2,4), Giorgio Cozzi (2), Stocco Gabriele (2,4), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics, University College London, United Kingdom. (2) Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy. (3) Department of Life Sciences, University of Trieste, 34127, Trieste, Itay. (4) Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Objectives: Ketamine (KET) is a potent agent for pediatric procedural sedation and anesthesia. Yet ketamine is burdened by adverse events (ADEs), including vomiting, agitation, and respiratory effects. Previous studies have reported that the rate of ketamine-related emesis in children ranges 6%–28%, depending on the size of the study 1 2. In fact, dosing of KET is suggested to be a predictor of ADEs1, however, a correlation between ADEs and drug exposure is not established. KET is metabolized in the liver by CYP450 3A4 and 2B6 enzymes 3, leading to the formation of norketamine (NOR), an active metabolite with anesthetic and analgesic effects. As NOR shows 30% potency compared to KET4, it is possible that the metabolite also contributes to the adverse event.Here we illustrate how Bayesian forecasting can be used to assess the correlation between systemic exposure and adverse events.
This study aimed to characterize the population pharmacokinetics of KET and NOR in a pediatric population receiving intravenous ketamine for analgosedation. With historical data on the safety profile of KET in older subjects undergoing similar analgosedation, an attempt was made to explore the potential correlation between drug exposure and vomiting and agitation, and identify high-risk groups, so that antiemetics may be administered prophylactically.
Methods: Pharmacokinetic and clinical data from a multicentre interventional, single arm study in children receiving a single intravenous bolus of ketamine as sole agent for analgosedation were available for the purpose of this investigation. Plasma concentrations of KET (N=55) and NOR (N=55) were collected within 2 hours after administration from 15 subjects. In addition, adverse event incidence from previous studies were used as priors to estimate the probability of KET-related vomiting and agitation.
Initially, a previously published model describing the disposition of KET with a first-order elimination and intermediate transit compartments for NOR formation5 was used as a reference (i.e., prior parameter distributions). Model development was implemented with a stepwise procedure, integrating both parent and metabolite into a single model. Model structure was refined by adding an allometric power model, with body weight as covariate on volume of distribution and clearance. Model performance was assessed by multiple diagnostics procedures. Predicted individual KET and NOR concentration vs time profiles were derived and used to calculate systemic exposure at different time points (AUCt) and peak concentrations (Cmax). The correlation between ADEs and KET and NOR levels was evaluated by comparing AUCt and Cmax in patients with or without ADEs across published studies. All modelling and simulation procedures were implemented in NONMEM v.7.5. Data handling, statistical and graphical summaries were performed in R.
Results: The median age was 11 years (range 1.0 – 17), median weight 44.0 kg (range 10-83). Patients received ketamine as a single intravenous bolus (median dose 50mg). Observed KET concentrations were slightly lower, but generally consistent with previous published data, whereas NOR levels were significantly lower. Vomiting was observed in 4 patients and agitation was observed in 2 patients. Body weight was the only significant covariate on disposition parameters. Genetic polymorphism in CY2B6 was found not to influence the metabolic clearance KET or NOR. Population parameter estimates for KET were CL=141 L/h (46.5% IIV), Vd= 44.2L (93.8% IIV), causing fast disappearance of the KET from plasma. NOR showed longer half-life, with formation and elimination clearances were CL= 10 L/h[CL1] and 16.7 L/h, respectively.
Although the model over-predicts the interindividual variability of NOR, the observed exposure, expressed in terms of AUC0-6h were similar for KET and NOR between patients with or without ADEs (KET: 0.34 vs 0.41 mg*h/L; NOR: 0.16 vs 0.21 mg*h/L). Complementary analysis of the ADE profile suggests that other covariates, including variable pharmacodynamic sensitivity to KET may explain the incidence of ADEs.
Conclusions: Despite high interindividual variability in the disposition of KET and NOR in pediatric patients undergoing analgosedation, the onset and occurrence of adverse events seems to be triggered by individual differences in the susceptibility to the effects of ketamine. This finding suggests that subjects at higher risk of vomiting cannot be identified using therapeutic drug monitoring.
References:
- Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54(2):171-180.e1-4. doi:10.1016/j.annemergmed.2009.04.004
- Suryaprakash S, Tham LP. Predictors of emesis in children undergoing procedural sedation with intramuscular ketamine in a paediatric emergency department. Singapore Med J. 2017;58(11):660-665. doi:10.11622/smedj.2016187
- Kharasch ED, Labroo R. Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology. 1992;77(6):1201-1207. doi:10.1097/00000542-199212000-00022
- Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203-207. doi:10.1093/bja/77.2.203
- Herd DW, Anderson BJ, Holford NHG. Modeling the norketamine metabolite in children and the implications for analgesia. Paediatr Anaesth. 2007;17(9):831-840. doi:10.1111/j.1460-9592.2007.02257.x
Reference: PAGE 32 (2024) Abstr 11196 [www.page-meeting.org/?abstract=11196]
Poster: Drug/Disease Modelling - Paediatrics