Victória Etges Helfer (1), Markus Zeitlinger (2), Bibiana Verlindo de Araújo (1), Teresa Dalla Costa (1)
(1) Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Brazil, (2) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Objectives: Ceftaroline fosamil (CPT-F), the prodrug of the β‐lactam ceftaroline (CPT), is a fifth-generation cephalosporine approved for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia [1]. Currently, the FDA recommended dose is 600 mg administered every 12 hours by IV infusion over 5 to 60 minutes [1]. In a previous study, a non-compartmental analysis of plasma and microdialysate concentrations in soft tissues of healthy volunteers after 600 mg every q8h and q12h as 2 or 1-hour IV infusions, respectively, showed similar free concentration profiles for muscle and subcutaneous tissues [2]. The aim of this analysis was the development of a compartmental population pharmacokinetic model to describe CPT tissue distribution and the impact of different dosing regimens on muscle and subcutaneous tissue free concentrations.
Methods: Data from twelve male healthy subjects (median age and body weight of 28 [range 24-50] years and 74.5 [63-106] kg) following CPT-F administration previously reported were used [2]. The subjects received single and multiple doses of either 600 mg q8h 2-hour IV infusion (n = 6) or 600 mg q12h 1-hour IV infusion (n = 6) of CPT-F (4 and 3 doses in total, respectively). Total plasma and free microdialysate CPT concentrations in muscle and subcutaneous tissue following the first and last doses (steady-state) were available, totalizing 844 data points. Data were analyzed with a nonlinear mixed effects modeling approach (NONMEM, version 7.4). The estimation method was the first-order conditional estimation method with interaction (FOCEI). To assess the model performance, graphical model evaluation techniques, such as goodness-of-fit plots and visual predictive checks (VPC) were used. Nonparametric bootstrapping (n=1000) was used to evaluate model stability and generate confidence intervals.
Results: Plasma concentrations of CPT were best described by a two-compartment model, with an assumption of 100% conversion of CPT-F into CPT and 20% plasma protein binding. Elimination clearance (CL) from central compartment was estimated to be 13.88 L/h [12.65-15.21] (mean [95% CI] from bootstrap), central volume of distribution (Vc) 18.38 L [16.56-20.22], intercompartmental clearance (Q) 5.16 L/h [4.10-6.61] and peripheral volume of distribution (Vp) 8.73 L [7.16-10.60]. Two additional compartments described the distribution into muscle and subcutaneous tissue with bi-directional transport parameterized as CLin and CLout. The apparent volumes of the additional compartments were fixed as 2.48 L and 2.31 L for muscle and subcutaneous, respectively. CLin was estimated to be 3.89 L/h [3.04-5.16] and 3.44 L/h [2.47-4.90], and CLout 7.34 L/h [6.01-9.27] and 5.85 L/h [4.44-7.62] for muscle and subcutaneous tissue, respectively. The model-estimated plasma to tissue penetration ratio (CLin/CLout = 0.53 and 0.59, for muscle and subcutaneous tissue, respectively) was in good agreement with NCA analysis [2]. The inter-individual variability (CV%) applying an exponential model for CL, Vc, CLin,muscle, and CLin,subcutaneous was 14.6%, 15.6%, 28.1%, and 31.6%, respectively. None of the covariates tested (weight, age, serum creatinine, and creatinine clearance) had substantial effects on CPT exposure. Model evaluation by VPC suggested that the proposed model was adequate with good precision.
Conclusions: A population PK model was successfully developed to describe plasma and soft tissue concentrations after two different dosing regimens in healthy volunteers. Both muscle and subcutaneous tissue showed similar exposures to CPT with about 50% to 60% of those in plasma. Further evaluations are needed to ascertain whether the increased infusion time with a short frequency of dosing of CPT-F is beneficial in comparison to the recommended dose.
References:
[1] Riccobene TA et al. Clin Pharmacol Ther (2021) 10(4), 420–427.
[2] Matzneller P et al. Antimicrob Agents Chemother (2016) 60, 3617–3625.
Reference: PAGE 29 (2021) Abstr 9704 [www.page-meeting.org/?abstract=9704]
Poster: Drug/Disease Modelling - Infection