Yaru Peng, Zeneng Cheng, Feifan Xie*
Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
Introduction: The pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy (CRRT) is complicated. The volume of distribution and clearance could be significantly altered by pathological factors, such as fluid overload, increased capillary permeability, acute kidney injury, and augmented renal clearance. Furthermore, the extracorporeal removal of a drug induced by CRRT makes the in vivo drug disposition difficult to estimate, and the extent of drug removal by CRRT shows wide variation[1]. Therefore, appropriate meropenem dosing in critically ill patients undergoing CRRT is challenging. Although the pharmacokinetics/pharmacodynamics (PK/PD) of meropenem in critically ill patients undergoing CRRT have been previously reported in several studies, the optimal dosing regimen of meropenem in this population remains undefined due to their small studied sample size, and uninformative analysis of the CRRT impact on the PK/PD target attainment (PTA).
Objectives: The present study aimed to perform a population PK/PD meta-analysis of meropenem using available literature data to inform the optimal treatment regimen in critically ill patients undergoing CRRT.
Methods: 501 meropenem concentrations in 78 adult CRRT patients pooled from nine published studies were used to develop the population PK model of meropenem[2-10]. Meropenem 0.5-2 g q6-12h was administered through short-term infusion (5-30 mins) to the patients. CRRT clearance was calculated for each patient based on the delivered CRRT dose (ranged from 15.9 to 33.6 mL/kg/h) and was incorporated as an independent component into total clearance of meropenem in the PK model. PK/PD target (40% and 100% fT>MIC) marker-based efficacy and risk of toxicity (trough concentration>45 mg/L) for empirically used dosing regimens (30 min infusion of 0.5-2 g q6-12h) of meropenem were evaluated by Monte Carlo simulation approach. The impact of CRRT dose and identified covariates on PTA and predicted toxicity was also examined.
Results: The median age of the 78 patients was 58.5 years, and the median body weight was 75 kg. Of these patients, 38 patients (48.7%) have anuria, and six of them suffered from severe trauma. Meropenem concentration data were adequately described by a two-compartment model with linear elimination. Trauma was identified as a pronounced modifier for the endogenous clearance of meropenem, explaining 40.5% inter-individual variability in endogenous clearance. The median values of total and endogenous clearances in non-trauma patients from different studies were at 3.03-6.16 L/h and 1.31-4.07 L/h, indicating great heterogeneities of clearance between studies. Simulations demonstrated that the targets of 40% and 100% fT>MIC (MIC ≤ 4 mg/L) could be achieved in non-trauma patients for meropenem regimens of 1-2 g q6-8h (100% PTA for 40%fT>MIC and over 90% PTA for 100%fT>MIC), but the risk of toxicity for the regimen of 2 g q6-8h was high (11.94-57.36% when CRRT dose is less than 35 mL/kg/h). The PTAs for meropenem dosing regimens under different CRRT dose intensities (25-50 mL/kg/h) are generally comparable, suggesting limited impact of CRRT dose on PTA. Besides, none of the simulated regimens in trauma patients obtained a PTA above 90%, indicating that short-term infusion administration of meropenem is inappropriate for this patient population.
Conclusions: A population PK model was developed for meropenem in CRRT patients. 1 g q6-8h meropenem may be an optimal option for empiric infection treatment in non-trauma CRRT patients with anuria.
References:
[1] Investigators RS. Renal replacement therapy for acute kidney injury in Australian and New Zealand intensive care units: a practice survey. Crit Care Resusc. 2008;10(3):225-30.
[2] Thalhammer F, Schenk P, Burgmann H, El Menyawi I, Hollenstein UM, Rosenkranz AR et al. Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrob Agents Chemother. 1998;42(9):2417-20.
[3] Kawano S, Matsumoto K, Hara R, Kuroda Y, Ikawa K, Morikawa N et al. Pharmacokinetics and dosing estimation of meropenem in Japanese patients receiving continuous venovenous hemodialysis. J Infect Chemother. 2015;21(6):476-8.
[4] Giles LJ, Jennings AC, Thomson AH, Creed G, Beale RJ, McLuckie A. Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration. Crit Care Med. 2000;28(3):632-7.
[5] Valtonen M, Tiula E, Backman JT, Neuvonen PJ. Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2000;45(5):701-4.
[6] Ververs TF, van Dijk A, Vinks SA, Blankestijn PJ, Savelkoul JF, Meulenbelt J et al. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration. Crit Care Med. 2000;28(10):3412-6.
[7] Langgartner J, Vasold A, Gluck T, Reng M, Kees F. Pharmacokinetics of meropenem during intermittent and continuous intravenous application in patients treated by continuous renal replacement therapy. Intensive Care Med. 2008;34(6):1091-6.
[8] Bilgrami I, Roberts JA, Wallis SC, Thomas J, Davis J, Fowler S et al. Meropenem dosing in critically ill patients with sepsis receiving high-volume continuous venovenous hemofiltration. Antimicrob Agents Chemother. 2010;54(7):2974-8.
[9] Isla A, Maynar J, Sanchez-Izquierdo JA, Gascon AR, Arzuaga A, Corral E et al. Meropenem and continuous renal replacement therapy: in vitro permeability of 2 continuous renal replacement therapy membranes and influence of patient renal function on the pharmacokinetics in critically ill patients. J Clin Pharmacol. 2005;45(11):1294-304.
[10] Robatel C, Decosterd LA, Biollaz J, Eckert P, Schaller MD, Buclin T. Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. J Clin Pharmacol. 2003;43(12):1329-40.
Reference: PAGE 30 (2022) Abstr 9952 [www.page-meeting.org/?abstract=9952]
Poster: Drug/Disease Modelling - Infection