Pharmacokinetics of cefoperazone/sulbactam in critically Ill thrombotic thrombocytopenic purpura patients undergoing therapeutic plasma exchange

Abstract

What is known and objectives The aim of this study was to investigate the pharmacokinetics (PK) of cefoperazone (CFP) and sulbactam (SUL) in critically ill thrombotic thrombocytopenic purpura (TTP) patients undergoing therapeutic plasma exchange (TPE). Methods Critically ill TTP patients receiving a dose of 3 g CFP/SUL (2.0 g/1.0 g) intravenously every 8 h were included in the study. TPE session began 10 min after the end of CFP/SUL infusion. Serial blood samples were collected at 0, 1, 2, 3, 4, 6 and 8 h at the fourth infusion with TPE and the sixth infusion without TPE. Effluent samples were collected at the effluent port of plasma eliminated at the end of TPE. Concentrations of CFP and SUL in plasma and effluent were measured using LC‐MS/MS. PK parameters were calculated based on two‐compartment open model. Results Five critically ill TTP patients receiving CFP/SUL monotherapy were enrolled. T1/2α of CFP and SUL with TPE was 0.62 and 1.30 h, respectively. For CFP, T1/2β with TPE were significantly higher than those without TPE (5.85 ± 3.16 vs. 4.41 ± 2.74, p = 0.016). Vss with TPE were significantly higher than those without TPE (7.23 ± 0.89 vs. 5.24 ± 0.80 L, p = 0.024). AUC0‐8 with TPE were significantly lower compared with those without TPE (1380.98 ± 411.99 vs. 1581.61 ± 500.22 mg*h/L, p = 0.011). Relatively, CLt with TPE were significantly higher than those without TPE (1.56 ± 0.46 vs. 1.37 ± 0.44 L/h, p = 0.010). For SUL, Vss and CLt were higher significantly with TPE than those without TPE (28.11 ± 8.42 vs. 18.87 ± 6.45 L, p = 0.002; 10.74 ± 2.01 vs. 8.60 ± 2.10 L/h, p = 0.048). Mean QPE of CFP and SUL were 344.42 ± 55.37 and 34.65 ± 10.09 mg, respectively. Mean fe% of CFP and SUL were 17.22 ± 2.77% and 3.46 ± 1.01%, respectively. What is new and conclusion TPE enhances the clearance of CFP and SUL in critically ill TTP patients. CFP is more likely to be removed than SUL due to its a low V and high Pb. TPE is suggested to begin 1–2 h after the end of CFP/SUL infusion. Plasma concentration monitoring is advised when CFP/SUL must be administered during TPE.

Research priorities for therapeutic plasma exchange in critically ill patients

“…So far, no studies have investigated undesired off-target effects of TPE as a results of unintentional removal, particularly not in critically ill patients with severely altered volumes of distribution. Along these lines, data on drug removal by TPE are scarce and mostly based on case reports or series; only a few pharmacokinetic studies have been performed [ 36 – 38 ], and for most drugs, there is no information available. Although kinetic models for the prediction of substance removal have been developed, drug dosing in TPE remains challenging and requires further research.…”