Shamir Kalaria1,2, Sarah Williford2, Dong Guo3, Yan Shu3, Christopher Medlin4, Matthew Li4, Siu Yan Amy Yeung2, Farhan Ali5, Wisna Jean5, Mathangi Gopalakrishnan1, Mojdeh Heavner4. 1. Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA. 2. Department of Pharmacy Services, University of Maryland Medical Center, Baltimore, Maryland, USA. 3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA. 4. Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA. 5. Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Abstract
BACKGROUND AND OBJECTIVES: Currently, no dosing information exists for ceftaroline fosamil in patients undergoing continuous renal replacement therapy (CRRT). The objectives of this study are to characterize the pharmacokinetics of ceftaroline in critically ill patients undergoing CRRT modalities and to derive individualized dosing recommendations. METHODS: This pharmacokinetic study aimed to enroll critically ill patients receiving ceftaroline fosamil and any CRRT modality from adult intensive care units. Selection of the specific CRRT modality and dosing regimen was based on clinical discretion. Pre-filter, post-filter, and ultrafiltrate samples were obtained before the administration of the fourth dose, after the completion of the infusion, and up to five additional time points post-infusion. Plasma concentrations were measured using a validated ultra-high performance liquid chromatography assay. Individual pharmacokinetic parameters were calculated using non-compartmental analysis. RESULTS: Four patients were enrolled to investigate the need for dosing adjustments. The average sieving coefficient for ceftaroline was 0.81 ± 0.1, indicating high filter efficiency. The average volume of distribution was 41.8 L (0.48 L/kg) and is within the previously reported range in patients with normal renal function. Non-renal clearance accounted for more than 50% of the total clearance observed in patients. The observed pharmacokinetic profiles suggest that the pharmacodynamic target for 2-log10 CFU reduction from baseline (%fT >1 mg/L of 50%) was met for each patient. Due to the impact of CRRT and non-renal clearance, dosing recommendations were derived for different ranges of effluent flow rates and adjusted body weights. For a patient with an adjusted body weight of 70 kg and receiving CRRT at an effluent flow rate of 3 L/h, a ceftaroline fosamil dosing regimen of 400 mg every 12 h is proposed. CONCLUSION: Ceftaroline is cleared extensively in critically ill patients receiving CRRT and may impact pharmacodynamic target achievement. Dose adjustments should be based on the intensity of the CRRT regimen, patient weight, and the clinical status of the patient.
BACKGROUND AND OBJECTIVES: Currently, no dosing information exists for ceftaroline fosamil in patients undergoing continuous renal replacement therapy (CRRT). The objectives of this study are to characterize the pharmacokinetics of ceftaroline in critically ill patients undergoing CRRT modalities and to derive individualized dosing recommendations. METHODS: This pharmacokinetic study aimed to enroll critically ill patients receiving ceftaroline fosamil and any CRRT modality from adult intensive care units. Selection of the specific CRRT modality and dosing regimen was based on clinical discretion. Pre-filter, post-filter, and ultrafiltrate samples were obtained before the administration of the fourth dose, after the completion of the infusion, and up to five additional time points post-infusion. Plasma concentrations were measured using a validated ultra-high performance liquid chromatography assay. Individual pharmacokinetic parameters were calculated using non-compartmental analysis. RESULTS: Four patients were enrolled to investigate the need for dosing adjustments. The average sieving coefficient for ceftaroline was 0.81 ± 0.1, indicating high filter efficiency. The average volume of distribution was 41.8 L (0.48 L/kg) and is within the previously reported range in patients with normal renal function. Non-renal clearance accounted for more than 50% of the total clearance observed in patients. The observed pharmacokinetic profiles suggest that the pharmacodynamic target for 2-log10 CFU reduction from baseline (%fT >1 mg/L of 50%) was met for each patient. Due to the impact of CRRT and non-renal clearance, dosing recommendations were derived for different ranges of effluent flow rates and adjusted body weights. For a patient with an adjusted body weight of 70 kg and receiving CRRT at an effluent flow rate of 3 L/h, a ceftaroline fosamil dosing regimen of 400 mg every 12 h is proposed. CONCLUSION: Ceftaroline is cleared extensively in critically ill patients receiving CRRT and may impact pharmacodynamic target achievement. Dose adjustments should be based on the intensity of the CRRT regimen, patient weight, and the clinical status of the patient.
Authors: Ana Alarcia-Lacalle; Helena Barrasa; Javier Maynar; Andrés Canut-Blasco; Carmen Gómez-González; María Ángeles Solinís; Arantxazu Isla; Alicia Rodríguez-Gascón Journal: Pharmaceutics Date: 2021-06-25 Impact factor: 6.321