title: Plasmafiltration as a possible contributor to kinetic targeting of pegylated liposomal doxorubicin (PLD) in order to prevent organ toxicity and immunosuppression.
abstract: OBJECTIVE
  To examine the removal of pegylated liposomal doxorubicin (PLD) during plasmafiltration (PF) and determine whether the drug could be withheld prior to its organ distribution responsible for mucocutaneous toxicity.
  
  
  METHODS
  Six patients suffering from platinum-resistant ovarian cancer were treated with a 1-h IV infusion 50 mg/m(2) of PLD/cycle-for three cycles q4w. Over 44 (46)-47(49) h postinfusion, five patients (14 cycles in total) underwent PF using a cascade PF method consisted of plasma separation by centrifugation and plasma treatment using filtration based one volume of plasma treatment, i.e., 3.18 L (±0.6 L) and plasma flow 1.0 L/h (0.91-1.48 L/h). Doxorubicin concentration in blood was monitored by a high-performance liquid chromatography method for 116 h postinfusion. Pharmacokinetic parameters determined from plasma concentration included volume of distribution, total body clearance, half-life of elimination, and area under the plasma concentration versus time. The amount of doxorubicin in the body eliminated by the patient and via extracorporeal treatment was evaluated. Toxicity was tested using CTCAE v4.0.
  
  
  RESULTS
  The efficacy of PF and early responses to PLD/PF combination strategy were as follows: over 44(46) h postinfusion considered necessary for target distribution of PLD to tumor, patients eliminated 46 % (35-56 %) of the dose administered. Over 44(46)-47(49) h postinfusion, a single one-volume plasma filtration removed 40 % (22-45 %) (Mi5) of the remaining doxorubicin amount in the body. Total fraction eliminated attained 81 % (75-86 %). The most common treatment-related adverse events (grade 1-2) such as nausea (4/14 cycles-28 %) and vomiting (3/14 cycles-21 %) appeared during 44 h postinfusion. Hematological toxicity-anemia (5/14 cycles-35 %) was reported after cycle II termination. Symptoms of PPE-like syndrome (grade 1-2) appeared in one patient concomitantly with thrombophlebitis and malignant effusion. In this study, only one adverse reaction (1/14-7 %) as short-term malaise and nausea was reported by the investigator as probably related to PF.
  
  
  CONCLUSIONS
  A single one-volume PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach. There were no serious signs of drug toxicity and/or PF-related adverse events. Kinetically guided therapy with pegylated liposomal doxorubicin combined with PF may be a useful tool to the higher efficacy and tolerability of therapy with PLD.
authors.affiliation: Department of Oncology and Radiotherapy, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Martínková
authors.affiliation: 4th Department of Internal Medicine - Hematology, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Bláha
authors.affiliation: Department of Oncology and Radiotherapy, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Kubeček
authors.affiliation: Department of Medical Biochemistry, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Maláková
authors.affiliation: Department of Gynecology, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Špaček
authors.affiliation: Department of Surgery, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Bezouška
authors.affiliation: Department of Biophysics, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Iva Selke
authors.initials: IS
authors.lastname: Krulichová
authors.affiliation: Department of Oncology and Radiotherapy, Charles University in Prague, Medical Faculty and University Hospital in Hradec Králové, Hradec Králové, Czech Republic. filip@fnhk.cz.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Filip
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D018450:Disease Progression; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000517:prevention & control*; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006207:Half-Life; D006440:Hemofiltration / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009367:Neoplasm Staging; D058958:Organs at Risk; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Kinetic targeting; Pegylated liposomal doxorubicin; Plasmafiltration