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

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, T1/2ß 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.

Effect of continuous venovenous haemodialysis on outcome and pharmacokinetics of arsenic species in a patient with acute promyelocytic leukaemia and acute kidney injury.

This study presents outcome and pharmacokinetics of arsenic trioxide (ATO) metabolites in patients on continuous venovenous haemodialysis (CVVHD). Of 3 acute promyelocytic leukaemia patients receiving CVVHD in management of acute kidney injury, only 1 patient was included. The patient presented disseminated intravascular coagulation and acute kidney injury before induction therapy was conducted. CVVHD was performed and ATO was initiated. Species of ATO metabolites in plasma and effluent were analysed using high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. Plasma concentrations of AsIII , monomethylarsonic acid and dimethylarsinic acid with CVVHD were lower than those without CVVHD. Area under the concentration-time curve from 0 to the last sample with quantifiable concentration of AsIII without CVVHD was significantly higher than that with CVVHD (292.10 ng h/mL vs 195.86 ng h/mL, P = .037), which were not observed for monomethylarsonic acid and dimethylarsinic acid. Dialysate saturation of arsenic species was remarkable, especially for AsIII . Complete remission was achieved and renal function recovered. In this study, ATO can be used safely and effectively to treat acute promyelocytic leukaemia patients undergoing CVVHD without dose adjustment.

Pharmacokinetics of cefoperazone/sulbactam in critically ill patients receiving continuous venovenous hemofiltration.

PURPOSE: Cefoperazone/sulbactam (CFP/SUL) is a ß-lactam/ß-lactamase inhibitor combination with little data available for the development of effective dosing guidelines during continuous renal replacement therapy. This study aimed to investigate the pharmacokinetics (PK) of cefoperazone/sulbactam in critically ill patients on continuous venovenous hemofiltration (CVVH). METHODS: A prospective, single-center, and open-label study was conducted. Critically ill patients receiving CVVH with 3 g cefoperazone/sulbactam (2.0/1.0 g) intravenously every 8 h were recruited. Serial blood and ultrafiltrate samples were paired collected for initial dose (occasion 1) and steady state (occasion 2). PK was assessed by non-compartmental analysis, and pharmacodynamics (PD) was evaluated by the percent of time for which drug concentrations exceed the minimum inhibitory concentration (%T >MIC). RESULTS: Total fourteen patients were enrolled. Volume of distribution at steady state (V ss) of cefoperazone and sulbactam for initial doses (20.8 ± and 28.4 L, respectively) increased significantly compared with those in healthy volunteers (P = 0.009 for CFP, P = 0.030 for SUL). Both cefoperazone and sulbactam showed significantly lower total clearance (CLt) (46.2 and 117.6 mL/min, respectively) compared with healthy volunteers (P = 0.000 for CFP, P = 0.017 for SUL). There is no significant difference in PK between occasion 1 and occasion 2 (P > 0.05). For occasion 1, mean CVVH clearance accounted for 34.3 and 33.9 % for CLt of cefoperazone and sulbactam, respectively. The minimum PD target of 60%T >MIC was achieved in seven of eight patients. For occasion 2, eight of nine patients achieved cefoperazone concentrations that were above the MIC for the entire dosing interval. CONCLUSIONS: PK of cefoperazone/sulbactam was altered in critically ill patients undergoing CVVH. Therapeutic drug monitoring would be recommended to individualize the dose regimen.

Monomethylarsonous acid binds to Cys-104α and Cys-112ß of hemoglobin in acute promyelocytic leukemia patients treated with arsenic trioxide.

Arsenic trioxide (As2O3) has prominent effect in treating acute promyelocytic leukemia (APL). Identification of arsenic-binding proteins has gained attention for their important biological functions. However, none has been published concerning the binding mechanism of arsenic with hemoglobin (Hb) in APL patients after treatment of As2O3. The present study discloses the binding sites of arsenic on Hb in APL patients. Concentrations of inorganic arsenic (iAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA) in erythrocytes of APL patients were quantified using HPLC-inductively coupled plasma-mass spectroscopy (HPLC-ICP-MS). Hb-bound arsenic was identified by size-exclusion chromatography ICP-MS. The binding sites of arsenic on Hb were determined by mass spectrometry (MS). The concentration trend of arsenic species in erythrocytes of 9 APL patients treated with As2O3 was iAs>MMA>DMA, and MMA was the predominant methylated arsenic metabolite. Size-exclusion chromatography separation of free and protein-bound arsenic by simultaneous monitoring of 57Fe and 75As demonstrated the presence of Hb-bound arsenic. MS information suggested monomethylarsonous (MMAIII) was the dominant arsenic bound to Hb, and further identified that Cys-104α and Cys-112ß were two binding sites of MMAIII in Hb. MMAIII binding to Cys-104α and Cys-112ß was responsible for arsenic accumulation in erythrocytes of APL patients. This interaction may contribute to understand the therapeutic effect of As2O3 as an anticancer drug and its toxicity on APL patients.

Monomethylated arsenic was the Major methylated arsenic in Red blood cells of acute promyelocytic leukemia patients treated with arsenic trioxide.

BACKGROUND: Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs. METHODS: Steady state blood samples were collected from 97 APL patients. H2O2 and HClO4 were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAsIII), arsenate (iAsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species. RESULTS: The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DMA (p < 0.01), while the concentration of DMA was significantly higher than iAs and MMA in plasma (p < 0.01). The correlation between iAs concentration in plasma and corresponding RBCs arsenic level was weak. And the concentrations of DMA and MMA in plasma were moderately positive correlated with those in RBCs. Hemoglobin-binding ratios of iAs, MMA and DMA were all over 70 %. CONCLUSIONS: In this study, we provided a reliable method to determine arsenic species in RBCs of APL patients treated with ATO by HPLC-HG-AFS. It was confirmed that the concentration of DMA is the highest in plasma, while MMA is the most predominant methylated arsenic in RBCs. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients.

Time course of arsenic species in red blood cells of acute promyelocytic leukemia (APL) patients treated with single agent arsenic trioxide.

BACKGROUND: Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). To elucidate metabolism and toxicity of arsenic, we analyzed time course of arsenic species in red blood cells (RBCs) of APL patients. METHODS: Nine APL patients received ATO (0.16 mg/kg/day) through 18-h infusion. Blood was collected before daily administration (days 2 to 9), and at different time points on day 8. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were detected by HPLC-ICP-MS. RESULTS: Arsenic species reached Cmax at 18 h on day 8. Arsenicals gradually accumulated during days 2 to 9, whereas their percentages remained almost constant. The general trend in red blood cells (RBCs) was iAs > MMA > DMA. MMA was consistently the predominant methylated arsenic metabolite in RBCs. iAs, MMA, and tAs (tAs = iAs + DMA + MMA) concentrations (P < 0.0001), MMA/DMA ratios (P = 0.0016) and iAs% (P = 0.0013) were higher in RBCs than in plasma. CONCLUSIONS: Time course of arsenic species reveal kinetic characteristic of ATO metabolites in RBCs. Arsenic species accumulated with administration frequency. Arsenic species in RBCs were remarkably different from those in plasma. Time course of arsenic species in RBCs is important in ATO clinical application.

Speciation analysis of arsenic in urine samples from APL patients treated with single agent As2O3 by HPLC-HG-AFS.

Arsenic trioxide [As2O3, arsenite (AsIII) in solution] has been applied successfully for the treatment of acute promyelocytic leukemia (APL). The arsenic speciation analysis of urine is critical to reveal the metabolic mechanism and the relationship between arsenic species and the clinical response. To characterize the arsenic species in urine, a simple and robust HPLC-HG-AFS method was developed and validated to quantify the levels of arsenic species [AsIII and its metabolites, monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), and arsenate (AsV)] in urine samples from 66 patients with APL. Patients received As2O3 (0.16 mg/kg/day) via continuous slow-rate infusion or conventional infusion. Urine samples were collected at steady state before the start of the next daily administration. The relative proportions (median) of arsenic species in urine were: AsIII, 33.00% (IQR: 24.34%-46.82%); DMAV, 36.42% (IQR: 25.82%-51.98%); MMAV, 23.89% (IQR: 19.52%-27.19%); and AsV, 2.22% (IQR: 1.293%-3.665%). The levels and proportions of arsenic species vary widely among individual patients. DMAV and un-metabolized AsIII were the dominant arsenic compounds excreted from the urine of patients with APL treated with As2O3. AsV was the least abundant arsenic species in all urine samples. Good positive correlations were found between the levels and proportions of arsenic species in urine and those in plasma; thus, urinary arsenic can reflect the levels of arsenic in plasma. Urinary arsenic is a critical biomarker to evaluate the metabolism and toxicity of arsenic in the clinical application of As2O3.

Clinical pharmacokinetics and safety profile of single agent arsenic trioxide by continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia.

PURPOSE: This study evaluated pharmacokinetics (PK) and safety profiles of single agent arsenic trioxide (ATO, As2O3) administrated as continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia. PATIENTS AND METHODS: Patients received 0.16 mg/kg ATO per day. ATO was given for 40 min infusion on the first day followed by 18-20 h daily at a very slow rate with infusion speed of 8 drips/min. During the first week, plasma samples were collected immediately before next administration on each day, and 0.5, 1, 2, 4, 8, 12 h after administration, at the end of infusion (18 h) on day 7. Total arsenic was determined by ICPMS. Arsenic species, arsenious acid (AsIII) and its metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were quantified by UHPLC-ICPMS. Safety assessment and PK analysis was conducted. RESULTS: Hyperleukocytosis occurred in two patients and no severe toxicity was observed. Total arsenic gradually accumulated from 15.84 to 34.12 ng/mL during the first week of therapy. MMAV/iAs increased and remained stable at value about 0.6 after day 4, while DMAV/MMAV declined under 2 after day 4. Compared with 2 h infusion, clearance (CL) of AsIII was significantly lower (0.8 ± 0.2 vs. 2.7 ± 1.7 L/kg/h, P = 0.002) while AUC0-t of AsIII was significantly increased (213.9 ± 38.6 vs. 82.6 ± 55.7 L/kg/h, P = 0.028). CONCLUSION: Continuous slow-rate ATO infusion provided an alternative administration for ATO therapy with few toxic effects. Degree of methylation from MMA to DMA is inconsistent with that from iAs to MMA. PK of arsenic species is considered important for clinical use of ATO.

Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia.

Hydroxyurea (HU) has been used in the treatment of chronic myeloid leukaemia (CML) and other myeloproliferative malignancies. Considering patient's wide variation in clinical response to HU, a new and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to monitor patients' compliance to treatment and investigate the pharmacokinetics of HU in patients with CML. Stable isotope labeled HU-13C1,15N2 was used as internal standard. Plasma samples were treated with acetonitrile to precipitate protein. The supernatant was injected directly without derivatization and separated on a hydrophilic interaction liquid chromatography column. HU was quantitatively analyzed with a mobile phase of acetonitrile-1.5mM ammonium formate (90:10, V:V) within 3min. The proposed method provided a linearity range of 1-200µg/mL. The coefficients of variation for intra- and inter-day precision were less than 2.07% and 4.28%, respectively, while the accuracy (bias) was in the range of -3.77 to 2.96%. This method was satisfactorily applied to the determination of HU in two patients with CML. It is suitable for supporting pharmacokinetic studies and clinical therapeutic monitoring.