Salvatore D'Agate, Oscar Della Pasqua
Clinical Pharmacology & Therapeutics Group, University College London, UK
Objectives: Herpes simplex virus (HSV) infection is uncommon amongst neonates, with an overall incidence of 9.6 cases per 100,000 live births in 2006 in the US.[1] Aciclovir is in many regards the prototypic agent against HSV infections. Currently, the doses of aciclovir IV for infusion in neonates is calculated based on body weight. Renal excretion is the major route of elimination of aciclovir and is dependent, in part, on active tubular secretion. Therefore, patients with impaired renal function require an appropriately modified dose, according to the degree of impairment. Limited attention has been given to the potential implications of immature renal function or to renal dysfunction due to the disease itself.[2, 3] The ultimate goal of this analysis was therefore 1) to characterise the population pharmacokinetics of aciclovir after IV administration to neonatal patients with or without suspected systemic infection and 2) to simulate the effect of variable renal function on the exposure to aciclovir taking into account the contribution of maturation (prematurity) and body weight on drug disposition.
Methods: A population pharmacokinetic model was developed using the data previously published by Sampson and colleagues.[4] Initially, model development was aimed at identifying an alternative parameterisation to disentangle the effect of size, maturation and organ function on clearance. In addition, we evaluated the role of disease on drug disposition by treating suspected systemic infection as a covariate factor. General model building criteria were applied to ensure that the appropriate structural PK model could be identified first. Final measures of model performance included visual predictive checks, bootstrapping, normalised prediction discrepancy error NPDE and mirror plots.
Using clinical trial simulations and extrapolation principles, a virtual patient cohort was created to explore the implications of age, body weight and renal function on aciclovir exposure. Relevant baseline characteristics along with a range of scenarios describing variable renal function, as defined by creatinine clearance were generated for the purposes of the analysis. Different dosing regimens were tested and compared to the currently recommended doses for patients aged 0 to 6 months. AUC, Cmax and T>IC90 values were derived and summarised. Simulation results were compared to exposure data in adults with variable renal function and newbors with renal dysfunction from previous publications.[5]
Results: Aciclovir exposure in neonatal patients was described by a 1-compartment model, with interindividual variability on disposition parameters and a proportional and additive error model. CL and V estimates were 0.31 (CI95% 0.11-1.91) L/h and 3.07 (CI95% 0.95-18.33) L, respectively. Covariates included in the final model were body weight, post-menstrual age and creatinine clearance on clearance and body weight and disease state on volume of distribution. Clinical trial simulations showed that alternative doses and dosing regimens may need to be considered when renal function is significantly reduced. Adjustments are suggested to the total daily dose whilst maintaining the dosing interval to a twice-daily regimen.
Conclusion: A suitable model parameterisation was identified, which discriminates between the changes in drug disposition associated with developmental growth, maturation, disease and organ function. Body weight and disease (systemic infection) were found to be statistically significant covariates on volume of distribution, whereas body weight, PMA, and CLCr had a significant effect on aciclovir clearance.
While there is no definitive consensus about the impact of confounding in creatinine clearance in newborns, our analysis shows dosing adjustment may be required to ensure patients are not treated sub-optimally. Simulated profiles show that systemic exposure to aciclovir can be achieved that are comparable levels to those observed in adults with renal impairment.
References:
[1] Flagg, E.W. and H. Weinstock, Pediatrics, 2011. 127(1): p. e1-8.
[2] Allegaert, K., M. van de Velde, and J. van den Anker, Paediatr Anaesth, 2014. 24(1): p. 30-8.
[3] Rodieux, F., et al., Clin Pharmacokinet, 2015. 54(12): p. 1183-204.
[4] Sampson, M.R., et al., Pediatr Infect Dis J, 2014. 33(1): p. 42-9.
[5] Englund, J. A., et al., J Pediatr, 1991, 119(1 Pt 1): 129-135.
Reference: PAGE 28 (2019) Abstr 9138 [www.page-meeting.org/?abstract=9138]
Poster: Drug/Disease Modelling - Paediatrics