Evaluating ceftazidime-avibactam exposure in patients undergoing automated peritoneal dialysis using population pharmacokinetic modelling
Maria Sanz Codina (1), Anh Duc Pham (2), Wisse van Os (1), Valentin al Jalali (1), Peter Matzneller (1, 5), Michael Wölfl-Duchek (1), Andreas Vychytil (3), Birgit Reiter(4), Thomas Stimpfl (4), J.G. Coen van Hasselt (2), Markus Zeitlinger (1)
(1) Department of Clinical Pharmacology, Medical University of Vienna, Austria, (2) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands, (3) Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria, (4) Clinical Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria, (5) Service of Rheumatology, South Tyrol Health System ASDAA-SABES, Italy
Introduction: Ceftazidime/Avibactam (CAZ/AVI) is a recently marketed beta-lactam/beta-lactamase inhibitor antimicrobial combination treatment indicated for use in complicated intra-abdominal infections, complicated urinary tract infections and hospital-acquired pneumonia. [1] Peritonitis is a common complication in patients undergoing automated peritoneal dialysis (APD). CAZ/AVI is a potential treatment option for APD patients with peritonitis. However, limited data exist on systemic and target-site pharmacokinetics (PK) at the site of infection in ADP patients.
Objectives: We aimed to develop a population PK model that will be used to evaluate the need for dose optimization for the treatment of APD-associated peritonitis with CAZ/AVI.
Methods: PK data was obtained from a Phase 1 trial in which 8 patients undergoing APD received a single dose of 2g ceftazidime/0.5g avibactam (CAZ-AVI) as an intravenous infusion over 2 hours. Included patients had a mean age of 52.4 ± 11 years, weight of 82.5 ± 17.3 kg, BMI of 27.1 ± 4.5 kg/m2 and creatinine clearance over 24 hours of 6.5 ± 7 mL/min. APD was started 16 hours after the beginning of the CAZ/AVI infusion. Total plasma, peritoneal fluid and urine samples were collected over 24 h. CAZ/AVI concentrations were quantified and to calculate the unbound concentrations of both drugs, we assumed a plasma protein binding of 10% for CAZ and 8% for AVI. [2] A nonlinear mixed effects modelling approach was used for analyzing the PK data using nlmixR v1.1.1.9 [3] with the first-order conditional estimation method (FOCE). Graphical evaluation of model fit was performed using goodness-of-fit plots and visual predictive checks (VPC).
Results: CAZ-AVI PK were best described using two separate two-compartment models. For both ceftazidime and avibactam, the first compartment describes plasma concentration with an elimination clearance (CL) and relative standard error (%RSE) of 0.921 L/h [20.3%] and 0.886 L/h [21%] from central with the volume of distribution (Vc) 29.5L [16%] and 33.3L [9.77%], respectively. The second compartment describes the distribution from plasma into the peritoneum described by intercompartmental clearance (Q) of 0.804 L/h [7.08%] and 0.999 L/h [10.4%]. The volume of the second compartments (Vp) was fixed at 2L. [4] Dialysate volume was added at the start of dialysis (16h) which was fixed at 0.465L. Inter-individual variability (CV%) was estimated for both CL (30.2% for CAZ and 37.3% for AVI) and Vc (31.5% for CAZ and 31.6% for AVI).
Conclusions: We developed a PK model to describe the CAZ/AVI concentration in plasma and peritoneal fluid of patients undergoing APD. Future steps will involve including the dialysis volumes and modelling the renal and dialysis clearance separately. The final model will be used to evaluate the need for further dose optimization for the treatment of APD-associated peritonitis with CAZ/AVI.
References:
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[2] Zavicefta Summary of Product Characteristics. 2016.
[3] Fidler M, Xiong Y, Schoemaker R, Wilkins J, Trame M, Hooijmaijers R, Post T WW. nlmixr: Nonlinear Mixed Effects Models in Population Pharmacokinetics and Pharmacodynamics. R package version 1.1.9. 2022.
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