Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin's Lymphoma.

PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients.

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC0-24) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC0-24 at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5'-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC0-24 for successful GI aGVHD prevention were .689 and 15.6 µg⋅hour⋅mL-1 for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC0-24 for neutrophil engraftment by day 25 was .405 µg⋅hour⋅mL-1. In conclusion, free MPA AUC0-24 may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC0-24 between .405 and .689 µg⋅hour⋅mL-1 could be considered informative of individualized MPA treatments in CBT patients.