Salvatore D'Agate, Flora Musuamba, Oscar Della Pasqua
Clinical Pharmacology & Therapeutics Group, University College London, UK
Objectives: The effectiveness of antibiotics in resource-limited settings has been determined by empirical evidence. Such an approach does not warrant optimal exposure of newborns to antibiotic agents, which are known to show different disposition characteristics in this population[1-5]. Here we externally validate a model for gentamicin in neonates and young infants[6] and assess the rationale for a simplified regimen of gentamicin taking into account the effect of size and organ maturation on pharmacokinetics. Using quantitative clinical pharmacology methods, and more specifically clinical trial simulations, we evaluate the impact of covariate factors on the disposition of gentamicin in pre-term and term infants aged 0 – 59 days. The ultimate goal of this analysis is to identify a simplified regimen for the use of gentamicin in resource-limited settings. The analysis is supported by efficacy data from a series of clinical trials in this population.
Methods: Clinical trial simulations were performed to characterise exposure to gentamicin after a q.d. regimen. A pharmacokinetic two-compartment model previously developed by Fuchs et al. [6] to describe the disposition of gentamicin in paediatric patients was used in conjunction with predicted gestational age as basis for the evaluation of the dose rationale for neonatal sepsis in a virtual cohort of neonates. The model was validated using an external dataset containing gentamicin pharmacokinetic data collected in neonates and young infants with or without sepsis. The external validation population included 29 newborns and infants with post-natal age between 1 – 148 days. Gentamicin exposure following once daily intramuscular administration was then simulated in a hypothetical population of 10000 children with ages varying from 0 to 59 days. In addition to the effect of demographic covariates, simulation scenarios have also accounted for the skewed distributions in age and body weight, which reflects the incidence and prevalence of sepsis in this population. The currently recommended dosing regimen by WHO was used as reference scenario for the purpose of comparisons between regimens[7]. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. All validation and simulations procedures were performed using NONMEM 7.3.
Results: The pharmacokinetic model showed acceptable predictive performance, accurately predicting gentamicin levels in the external validation population. Simulation scenarios revealed that in contrast to the WHO guidelines, which recommend 5-7.5 mg/kg dose, gentamicin can be used as a fixed dosing regimen according to three weight-bands: 8mg for patients with body weight <2.5 kg [Cmax: 12.6 (9.9 – 19.9) mg/L, Cthrough: 0.65 (0.08 – 1.47) mg/L], 16mg for patients with body weight between 2-4 kg [Cmax: 13.1 (9.5 – 22.6) mg/L, Cthrough: 0.92 (0.24 – 2.06) mg/L], and 30mg for those with body weight >4 kg [Cmax: 15.2 (12.3 – 18.9) mg/L, Cthrough: 0.80 (0.21 – 2.70) mg/L]. Despite correction for differences in body weight, the recommended regimens by the WHO do not fully correct for the changes in drug disposition, with some children remaining significantly below the target threshold for peak concentrations.
Conclusion: Our analysis shows how empirical dose recommendations can be assessed in a systematic manner, taking into account the contribution of factors known to affect drug disposition in the neonatal patient population. Most importantly, the results from clinical trial simulations indicate that in resource-limited settings, neonates and young infants with sepsis aged 0-59 days can be treated with a simplified regimen of gentamicin.
References:
[1] Manolis, E. and G. Pons, Br J Clin Pharmacol, 2009. 68(4): p. 493-501.
[2] Pandolfini, C., et al., Eur J Clin Pharmacol, 2013. 69(4): p. 1031-6.
[3] Pineda, L.C. and K.M. Watt, Clin Perinatol, 2015. 42(1): p. 167-76, ix-x.
[4] Roberts, J.K., et al., Clin Pharmacokinet, 2014. 53(7): p. 581-610.
[5] Stockmann, C., et al., Paediatr Drugs, 2014. 16(1): p. 67-81.
[6] Fuchs, A., et al., Br J Clin Pharmacol, 2014. 78(5): p. 1090-101.
[7] World Health Organization. Guideline: Managing possible serious bacterial infection in young infants when referral is not feasible. 2015 [cited 2018 21 Jun]; Available from: http://apps.who.int/iris/bitstream/10665/181426/1/9789241509268_eng.pdf
Reference: PAGE () Abstr 9478 [www.page-meeting.org/?abstract=9478]
Poster: Clinical Applications