Salvatore D’Agate and Oscar Della Pasqua
University College London, London, UK
Objectives: To assess the feasibility of a simplified regimen for amoxicillin in pre-term and term infants (0 – 59 days) with sepsis in resource-limited settings taking into account the impact of covariate factors on systemic drug exposure.
Methods: The approach was based on the adaptation of an existing model developed by Carlier et al [1] in which the PK of amoxicillin has been characterised in critically ill adults. To account for the effect of differences in size, the model was integrated with the extrapolation approach proposed by Zhao et al[2], which relies on allometric concepts. The impact of other relevant demographic and clinical covariate factors was then evaluated using data from recent efficacy trials in the target population, which also served as a reference for the purposes of our analysis. NLME modelling was performed using NONMEM V7.3. Model performance was assessed by diagnostic and GOF criteria. Clinical trial simulations were then implemented to explore the feasibility of a simplified dosing regimen was based on the assumption that comparable drug exposure should be attained across the overall patient population, irrespective of age, body weight or disease severity. Measures of exposure to amoxicillin included the plasma concentration vs. time profile, Cmin, Cmax, AUC vs. time curve and time above MIC (T>MIC). Given the clinical evidence of the relevance of T>MIC for amoxicillin, target concentration values were selected to maximise this parameter.
Results: Amoxicillin PK was best described by a two compartment model with first order absorption and elimination. Birth weight, post-natal age and serum albumin concentration were identified as significant covariates affecting amoxicillin clearance whereas body weight and sepsis (disease state) were found to affect the volume of distribution of central and peripheral compartments. Body weight showed a significant effect on the inter-compartmental clearance. The predicted exposure to amoxicillin in a cohort of virtual patients with demographic characteristics comparable to the reference trials shows that target levels can be achieved across the overall population by using fixed dose in combination with two weight bands, namely: 1) 250 mg for patients < 4.0 kg and 500 mg patients >4.0 kg.
Conclusion: A fixed dosing regimen will warrant target drug levels during the dosing interval, minimising the risk of sub-optimal exposure in patients with low body weight. Further evidence of the suitability of the proposed doses should be obtained by prospective evaluation of PK in target population.
References:
[1] Carlier M, Noe M, De Waele JJ, Stove V, Verstraete AG, Lipman J, Roberts JA. Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients. The Journal of antimicrobial chemotherapy 2013; 68: 2600-8.
[2] Zhao W, Biran V, Jacqz-Aigrain E. Amikacin maturation model as a marker of renal maturation to predict glomerular filtration rate and vancomycin clearance in neonates.
Reference: PAGE 25 (2016) Abstr 6015 [www.page-meeting.org/?abstract=6015]
Poster: Drug/Disease modeling - Paediatrics