Umberto Villani
Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom
Objectives: Ceftriaxone is a third-generation cephalosporin exhibiting antimicrobial properties for a broad spectrum of bacteria. In both paediatric and adult patients, it is currently used as a treatment for various pathologies, such as urinary and respiratory tract infections, septicaemia and meningitis [1]. It has also been proven effective in treating nosocomial infections caused by pathogens resistant to multiple drugs [2]. However, to date few studies have explored pharmacokinetics (PK) of ceftriaxone in neonates. Allometric scaling has been commonly used to extrapolate pharmacokinetics from adults to children [3]. It is however unclear whether such scaling techniques allow for an accurate prediction of drug disposition in younger children, for whom organ maturation plays a fundamental role. Thus, the objectives of the current study were the following: 1) to characterise the population PK of ceftriaxone in neonates and children based on an optimised, sparse blood sampling scheme, taking into account the effect of developmental growth and organ maturation, and (2) to evaluate the probability of target attainment following standard and alternative dosing regimens for the proposed indications.
Methods: A study was performed for the collection of sparse pharmacokinetic data in neonates and children (age range: 1month-12years) receiving an intravenous infusion of 21-70 mg/kg ceftriaxone. The study was implemented at the Clinical Hospital of the Faculty of Medicine of Ribeirão Preto following approval by the local ethics committee and after informed consent was given by parents and/or legal guardians.
Ceftriaxone PK data analysis was based on priors from model parameter distributions from a PK model in adult subjects in conjunction with allometric scaling and organ maturation concepts to describe the exposure in the paediatric population. Demographic characteristics and clinical measures were also evaluated as potential covariate factors on drug disposition parameters. Standard model diagnostics were employed to evaluate the performance of the final model. Microbiological susceptibility data was used to assess the probability of target attainment under the assumption that efficacy is driven by the time above the minimal inhibitory concentration (T>MIC) of at least 40% of the dosing interval. Potential differences between estimates of model parameters in adults and pediatric populations were also assessed.
In addition, external validation of the PK model was then performed using data from neonates and paediatric patients (N=12, aged 1day -12years) enrolled into an observational, prospective, single centre study. The mean prediction error (MPE) and the root mean squared error (RMSE) were computed to quantify accuracy and precision of population and individual post-hoc predictions. Initial dosing recommendations were then computed using post-hoc predictions from this group of patients.
Parameter estimation and post-hoc analysis was conducted using NONMEM 7.5 and PsN 5.2.6. All exploratory data analyses were performed using R version 4.1.2.
Results: The PK of ceftriaxone in neonates and children was described by a two- compartment model, including the effect off body weight on clearance and volume of distribution, as well as post-menstrual age on systemic clearance. Weight normalised estimates (interquartile interval) were 2.26 (1.97 – 2.92) L/h/70 kg and 13.3 (12.0 – 16.3) L/70kg for clearance and volume of distribution, respectively. These results contrast with the disposition of ceftriaxone in adults, for whom values of 0.93 (0.67 – 1.11) L/h/70 kg and 4.68 (4.28 -5.98) L/70kg were observed for clearance and volume of distribution. The predictive performance of the model was deemed appropriate according to VPCs, RMSE and MPE estimates.
Conclusions: We have identified a suitable parameterisation that takes into account developmental growth and organ maturation processes, allowing for accurate prediction of ceftriaxone PK in neonates and children. Different dosing regimens need to be considered depending on microbiological susceptibility to ensure high probability of target attainment and microbiological cure in this population. Based on total concentrations, doses of 80 to 100 mg/kg ceftriaxone should be recommended to achieve maximum target attainment at MIC < 16 mg/L for T>MIC > 50% of the dosing interval.
References:
[1] M. C. Nahata and W. J. Barson, “Ceftriaxone: A third-generation cephalosporin,” Drug Intelligence and Clinical Pharmacy, vol. 19, no. 12. 1985.
[2] H. M. Lamb, D. Ormrod, L. J. Scott, and D. P. Figgitt, “Ceftriaxone: An update of its use in the management of community-acquired and nosocomial infections,” Drugs, vol. 62, no. 7. 2002.
[3] B. J. Anderson and N. H. G. Holford, “Mechanism-based concepts of size and maturity in pharmacokinetics,” Annual Review of Pharmacology and Toxicology, vol. 48. 2008.
Reference: PAGE 30 (2022) Abstr 10203 [www.page-meeting.org/?abstract=10203]
Poster: Drug/Disease Modelling - Infection