Pegylovaný lipozomální doxorubicin je doxorubicin hydrochlorid enkapsulovaný v lipozomech stabilizovaných vrstvou polyethylenglykolu. Ve srovnání s nelipozomální formou doxorubicinu enkapsulace doxorubicinu v lipozomech významně ovlivňuje farmakokinetické vlastnosti cytostatika. Umožňuje pomalejší uvolňování účinné látky, snížení výskytu nežádoucích účinků, přičemž protinádorová účinnost je zachována. Výhodou přípravku je omezená kardiotoxicita, naopak častěji je popisován výskyt palmárně-plantární erytrodysestezie (tzv. hand-foot syndrom) [1, 2]. Doxorubicin narušuje DNA interkalací antracyklinové části, chelací kovových iontů nebo generováním volných radikálů. Doxorubicin působí též inhibici topoizomerázy II, která je kritickou strukturou pro funkci DNA. Cytotoxická účinnost je relativně nezávislá na fázi buněčného cyklu. Pegylovaný lipozomální doxorubicin je indikován v monoterapii nemocných s metastazujícím karcinomem prsu, u kterých je zvýšené kardiální riziko. Dále je indikován k léčbě pokročilého ovariálního karcinomu při selhání chemoterapie cytostatiky na bázi platiny jako léčby první volby a pro léčbu Kaposiho sarkomu sdruženého s AIDS. V kombinaci s bortezomibem může být pegylovaný lipozomální doxorubicin použit k léčbě progredujícího mnohočetného myelomu.

Pegylated liposomal doxorubicin is a liposome-encapsulated form of the hydrochloride salt of doxorubicin enclosed within a polyethylene glycol layer. The liposome-encapsulated doxorubicin differs considerably from the non-liposomal formulation in pharmacokinetic properties. The former releases the active ingredient at a slower rate and reduces adverse effects while the anti-tumor potential is preserved. The major benefit of pegylated liposomal doxorubicin is reduction in induced cardiotoxicity but it has the disadvantage of causing more frequently hand foot syndrome, i.e. palmar-plantar erythrodysesthesia [1, 2]. Doxorubicin is known to interact with DNA by intercalation, metal ion chelation or generation of free radicals. It also inhibits topoisomerase II which is critical for DNA function. The cytotoxic potential is relatively independent of cell cycle phase. Pegylated liposomal doxorubicin is indicated as monotherapy in patients with metastatic breast cancer who are at higher cardiac risk. It is also indicated for use in the treatment of advanced ovarian cancer refractory to first-line platin-based chemotherapy and AIDS associated Kaposi's sarcoma. In combination with bortezomib it can be used in the treatment of advanced multiple myeloma.

• MeSH
• antitumorózní látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• farmakokinetika MeSH
• Kaposiho sarkom farmakoterapie   MeSH
• kombinovaná farmakoterapie MeSH
• lékové interakce imunologie   MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   MeSH
• nádory prsu farmakoterapie   MeSH
• nádory vaječníků farmakoterapie   MeSH
• nežádoucí účinky léčiv imunologie   krev   MeSH
• těhotenství účinky léků   MeSH
• Check Tag
• lidé MeSH
• těhotenství účinky léků   MeSH

• MeSH
• doxorubicin analogy a deriváty   MeSH
• nádory prsu farmakologie   MeSH
• nádory vaječníků farmakologie   MeSH
• nádory farmakologie   MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• farmacie a farmakologie
• onkologie

Ovarian cancer is the fifth most common malignancy in the world's female population and with the highest lethality index among gynecological tumors. The prognosis of metastatic disease is usually poor, especially in platinum-resistant cases. There are several options for the treatment of metastatic disease resistant to platinum derivates (e.g. paclitaxel, topotecan and pegylated liposomal doxorubicin), all of which are considered equipotent. Pegylated liposomal doxorubicin (PLD) is a liposomal form of the anthracycline antibiotic doxorubicin. It is characterized by more convenient pharmacokinetics and a different toxicity profile. Cardiotoxicity, the major adverse effect of conventional doxorubicin, is reduced in PLD as well as hematotoxicity, alopecia, nausea and vomiting. Skin toxicity and mucositis, however, emerge as serious issues since they represent dose and schedule-limiting toxicities. The pharmacokinetics of PLD (prolonged biological half-life and preferential distribution into tumor tissue) provide new possibilities to address these toxicity issues. The extracorporeal elimination of circulating liposomes after PLD saturation in the tumor tissue represents a novel and potent strategy to diminish drug toxicity. This article intends to review PLD characteristics and the importance of extracorporeal elimination to enhance treatment tolerance and benefits.

• MeSH
• antibiotika antitumorózní krev   terapeutické užití   MeSH
• chemorezistence MeSH
• cytostatické látky MeSH
• doxorubicin analogy a deriváty   krev   terapeutické užití   MeSH
• lidé MeSH
• mimotělní oběh * MeSH
• nádory vaječníků krev   farmakoterapie   MeSH
• polyethylenglykoly terapeutické užití   MeSH
• sloučeniny platiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

PURPOSE: 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. CONCLUSION: 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.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   škodlivé účinky   krev   farmakokinetika   MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   analogy a deriváty   krev   farmakokinetika   MeSH
• hemofiltrace škodlivé účinky   metody   MeSH
• kritické orgány MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolická clearance MeSH
• nádory vaječníků * farmakoterapie   patologie   MeSH
• nádory vejcovodů * farmakoterapie   patologie   MeSH
• nežádoucí účinky léčiv etiologie   prevence a kontrola   MeSH
• plocha pod křivkou MeSH
• poločas MeSH
• polyethylenglykoly aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• progrese nemoci MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• doxorubicin škodlivé účinky   terapeutické užití   MeSH
• hepatocelulární karcinom farmakoterapie   MeSH
• indukovaná hypertermie využití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   MeSH
• farmakoterapie metody   MeSH
• indukovaná hypertermie MeSH
• lidé MeSH
• medulární karcinom MeSH
• nádory prsu patologie   MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

PURPOSE: The present study evaluates the safety and efficacy of double-plasma filtration (PF) to remove the exceeding pegylated liposomal doxorubicin (PLD) in circulation, thus reducing mucocutaneous toxicity. METHODS: A total of 16 patients with platinum-resistant ovarian cancer were treated with 50 mg/m2 PLD applied in 1-h IV infusion every 28 days. PF was scheduled at 44-46 h post-infusion. The concentration of plasma PLD and non-liposomal doxorubicin (NLD) was monitored with high-performance liquid chromatography at 116 h post-infusion. A non-linear method for mixed-effects was used in the population pharmacokinetic model. The dose fraction of PLD eliminated by the patient prior to PF was compared with the fraction removed by PF. PLD-related toxicity was recorded according to CTCAE v4.0 criteria and compared to historical data. Anticancer effects were evaluated according to RECIST 1.1 criteria. RESULTS: The patients received a median of 3 (2-6) chemotherapy cycles. A total of 53 cycles with PF were evaluated, which removed 31% (10) of the dose; on the other hand, the fraction eliminated prior to PF was of 34% (7). Exposure to NLD reached only 10% of exposure to the parent PLD. PLD-related toxicity was low, finding only one case of grade 3 hand-foot syndrome (6.7%) and grade 1 mucositis (6.7%). Other adverse effects were also mild (grade 1-2). PF-related adverse effects were low (7%). Median progression-free survival (PFS) and overall survival (OS) was of 3.6 (1.5-8.1) and 7.5 (1.7-26.7) months, respectively. Furthermore, 33% of the patients achieved stable disease (SD), whereas that 67% progressed. CONCLUSION: PF can be considered as safe and effective for the extracorporeal removal of PLD, resulting in a lower incidence of mucocutaneous toxicity.

• MeSH
• antibiotika antitumorózní škodlivé účinky   MeSH
• dospělí MeSH
• doxorubicin škodlivé účinky   analogy a deriváty   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory vaječníků farmakoterapie   MeSH
• nežádoucí účinky léčiv farmakoterapie   MeSH
• organoplatinové sloučeniny terapeutické užití   MeSH
• polyethylenglykoly škodlivé účinky   MeSH
• prospektivní studie MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS: Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050-6. © 2016 American Cancer Society.

• MeSH
• bortezomib aplikace a dávkování   terapeutické užití   MeSH
• doxorubicin aplikace a dávkování   analogy a deriváty   terapeutické užití   MeSH
• intravenózní podání MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• mnohočetný myelom farmakoterapie   mortalita   MeSH
• polyethylenglykoly aplikace a dávkování   terapeutické užití   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   terapeutické užití   MeSH
• rozvrh dávkování léků MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

INTRODUCTION: Nanoparticle-based drug delivery systems can overcome the dose-limited toxicity of cytostatics. Pegylated doxorubicin-containing liposomes (PLD) are able to reduce cardiotoxicity. PLD quickly (in 2 days) attains therapeutic concentration in tumorous tissue (kinetic targeting), while its distribution in normal tissue, which is a cause of mucocutaneous toxicity (MCT), is delayed. We examined PLD extracorporeal removal effectivity, using plasma filtration (PF) to determine whether the drug could be withheld prior to its organ distribution responsible for MCT toxicity. METHODS: Nine patients suffering from platinum-resistant ovarian cancer were treated with a infusion of 50 mg/m2of PLD/cycle - for four cycles q4w. Over 44 (46)-47 (49) hours postinfusion, the patients (14 cycles in total) underwent PF using the cascade method. Doxorubicin blood concentration was monitored by the HPLC method during 116 h. Individual pharmacokinetic parameters of doxorubicin were estimated. RESULTS: Over 44 (46)-47 (49) hours postinfusion, a single one-volume plasma filtration removed 35 (22-45) % of the remaining doxorubicin amount in the body. Symptoms of MCT - PPE-like syndrome (grade 3) appeared in one patient. Only one adverse reaction (1/14-7%) - short-term malaise and nausea - was reported as being related to PF. CONCLUSION: PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach, which can be a useful tool for the increased efficacy and tolerability of therapy with PLD. There were no serious signs of drug toxicity and/or PF-related adverse events.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   škodlivé účinky   krev   farmakokinetika   MeSH
• chemorezistence MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   analogy a deriváty   krev   farmakologie   MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory vaječníků krev   diagnóza   farmakoterapie   MeSH
• polyethylenglykoly aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• příprava léků MeSH
• senioři MeSH
• tkáňová distribuce MeSH
• výměna plazmy metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Cytostatic treatment is often negatively affected by dose-limited toxicities. Novel agents, including nanoparticle-based drug delivery systems (DDS), are becoming available to overcome this problem. Despite achieving a lesser toxicity in exchange for more favorable pharmacokinetic profiles, the use of DDS is often associated with a particular toxicity profile. The accumulation of DDS in tumor tissue is much faster than in normal tissues where toxic events occur. While only a small amount of DDS is delivered to the target tissue, and accumulated there, most of the administered dose remains in circulation. The removal of this fraction, which is no longer effective, is thought to reduce toxicity. Pegylated liposomal doxorubicin (PLD) has been proven to be effective in platinum-resistant ovarian carcinoma with the reduced risk for cardiotoxicity. Once saturation in tumor tissue is achieved, prolonged circulation seems ineffective, whereas other toxicity risks (palmar-plantar erythrody sesthesia and mucositis) have been reported. Therefore, extracorporeal elimination of circulating nanoparticles using plasma filtration would probably reduce this risk of toxicity. The elimination rate could be kinetically regulated, i.e. based on individual doxorubicin pharmacokinetic variables. Plasma filtration can significantly influence the exposure to PLD (plasma concentration-time profile-AUC of PLD) and would be a suitable, well tolerated method enabling individualized, more effective and safer chemotherapy.

• Klíčová slova
• plasma filtration, liposomal doxorubicin,
• MeSH
• antibiotika antitumorózní škodlivé účinky   terapeutické užití   MeSH
• doxorubicin * analogy a deriváty   farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• mukozitida chemicky indukované   prevence a kontrola   MeSH
• nádory farmakoterapie   MeSH
• polyethylenglykoly farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• separace krevních složek * metody   MeSH
• syndrom ruka-noha etiologie   prevence a kontrola   MeSH
• systémy cílené aplikace léků * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH