Farmakokinetika metotreksata kod dece

Abstract

Metotreksat kao antagonista folne kiseline ima široku upotrebu za lečenje brojnih maligniteta, primenjen u visokim dozama i u kombinciji sa leukovorinom. Iako je terapija visokim dozama metotreksata drastično poboljšala prognozu pacijenata sa malignitetom, teški neželjeni efekti terapije predstavljaju stalan klinički problem. Ciljevi istraživanja bili su određivanje serumske koncentracije metotreksata i izračunavanje farmakokinetičkih parametara metotreksata kod dece obolele od malignih bolesti koja su na terapiji visokim dozama metotreksata (2 g/m2 i 5 g/m2 ); ispitivanje postojanja uticaja primenjene doze metotreksata, demografskih i kliničkih karakteristika ispitanika na koncentracije i farmakokinetičke parametare. Ispitivano je prisustvo i stepen kliničkih i laboratorijskih znakova toksičnosti metotreksata, kao i uticaj primenjene doze metotreksata i demografskih karakteristika ispitanika na pojavu i stepen toksičnosti . U okviru retrospektivno - prospektivne studije ukjučeno je četrdeset i dva pedijatrijska pacijenta uzrasta od 0,75 do 17,75 godina (medijana 5,75 godina). Svi pacijenti su lečeni u Službi za hematologiju i onkologiju Instituta za zdravstvenu zaštitu dece i omladine Vojvodine (Novi Sad, Srbija) u periodu od juna 2004. godine do juna 2012. godine. Trideset i osam ispitanika je lečeno pod dijagnozom akutne limfoblastne leukemije prema dva uzastopna protokola ALL IC - BFM 2002 i ALL IC - BFM 2009 Internacionalne BFM studijske grupe „I - BFM - SG“ (International Berlin -Frankfurt - Münster Study Group) za proučavanje i lečenje dečje non-B akutne limfoblastne leukemije. Četvoro je imalo dijagnozu non - Hodgkin limfoma i bili su uključen i u protokol NHL - BFM 95. Istraživanje je obuhvatilo 113 ciklusa terapije metotreksatom (1– 4 ciklusa po pacijentu) sa 386 izmerenih serumskih koncentracija metotreksata. Raspon primenjenih doza metotreksata kretao se od 800 do 10.000 mg. Koncentracije metotreksata su merene 24, 36 i 42 sata nakon započinjanja infuzije metotreksata, a po potrebi i u dužim vremenskim intervalima. Za izračunavanje farmakokinetičkih parametara korišćen je dvokompartmanskih farmakokinetički model posle obustavljanja intravenske infuzije, gde postoje relacije za farmakokinetičke tačke. Podaci o kliničkim i laboratorijskim znacima toksičnosti metotreksata prikupljani su iz medicinske dokumentacije, a za stepenovanje toksičnosti korišćen je skor sistem - Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, U.S. Department of health and human services, National Institute of Health, National Cancer Institute. U cilju utvrđivanju uticaja karakteristika ispitanika, primenjene doze i prisustva produžene eliminacije na posmatrane parametre, vršeno je poređenje tri grupe pacijenata (doza 2 g/m2 bez produžene eliminacije, 5 g/m2 bez produžene liminacije i 5 g/m2 sa produženom eliminacijom metotreksata). Za celokupnu grupu ispitanika, medijane koncentracije metotreksta bile su 25,82 μmol/l u 24. satu, 0,68 μmol/l u 36. satu i 0,24 μmol/l u 42. satu merenja. Najizraženija interindividualna varijabilnost u koncentracijama metotreksata bila je u 42. satu merenja, dok je intraindividualna varijabilnost bila najizraženija u 36. satu merenja. Medijana klirensa metotreksata bila je 8,32 l/h. Farmakokinetički parametri redom bili su: medijana volumena centralnog kompartmana V1 28,47 l, medijane konstanti k10 0,206, k12 0,0245, k21 0,1114. Najizraženiji uticaj primenjene doze na koncentracije metotreksata pokazan je u 24. satu merenja, dok uticaj doze na klirens metotreksata nije pokazan. Prisustvo produžene eliminacije metotreksata dovodi do smanjenih vrednosti konstanta k10 i k21. Nije pokazana statistički značajna interakcija ispitivanih demografskih karakteristika (uzrast, telesna površina i pol) i koncentracija metotreksata, kao ni klirensa metotreksata. Pokazana je značajna interakcija između koncentracija metotreksata i nivoa laktat dehidrogenaze, kao i klirensa metotreksata i nivoa kreatinina i laktat dehidrogenaze. Većina ispoljenih toksičnosti bila je umerenog stepena (<3 stepena). Najzastupljeniji klinički znak toksičnosti bio je oralni mukozitis, koji je bio većeg stepena u grupi sa većom primenjenom dozom metotreksata (5g/m2). Najzastupljeniji laboratorijski toksični efekti metotreksata bili su leukopenija i anemija. Najteži stepeni laboratorijskih znakova toksičnosti (leukopenija, anemija, porast AST, ALT i GGT) nalazili su se u grupi sa većom dozom (5 g/m2) i sa produženom eliminacijom metotreksata. Osnov za kliničko vođenje pacijenata na terapiji visokim dozama metotreksata je terapijsko praćenje leka (therapeutic drug monitoring – TDM) zbog velikih interindividualnih i intraindividualnih varijabilnosti u farmakokinetici leka. Rutinsko praćenje koncentracija metotreksata važno je za identifikaciju pacijenata sa povećanim rizikom od razvoja toksičnosti , te je TDM standardna praksa za smernice spasavanja leukovorinom, naročito za pacijente za koje se zna da imaju smanjen klirens metotreksata ili druge rizike povezane sa prolongiranim citotoksičnim koncentracijama (bubrežna ili jetrena oštećenja, kolekcije tečnosti u “trećem prostoru”, gastrointestinalna opstrukcija). Veliki broj istraživanja kod pedijatrijskih pacijenata pokazao je vezu između sistemskog izlaganja metotreksatu i efikasnosti i toksiĉnosti metotreksata. Ipak, ne postoji dovoljno informacija o farmakokinetici metotreksata kod dece obolele od akutne limfoblastne leukemije. Takođe, ova istraživanja nisu do sada sprovođena kod dece koja su lečena u našoj sredini.

Methotrexate is an antifolate drug widely used for treatment of various malignant tumours. It is used at high doses and in combination with leucovorin rescue. Although high - dose MTX therapy dramatically improves the prognosis of patients with malignancies, severe adverse events are constant clinical concern. The aims of this stydy were to determine the serum concentration of methotrexate and to calculate the pharmacokinetic parameters of methotrexate in children suffering from malignant deseases who are treated with high doses of metotrexate (2 g/m2 i 5 g/m2 ); furthermore, to investigate the effects of the applied doses of methotrexate, and demographic and clinical characteristics of the examinees on the concentration and pharmacokinetic parameters of the drug. The study investigated the presence and the degree of clinical and laboratory signs of metotrexate toxicity, as well as the effect of the applied doses, and demographic characteristics of the examinees on the appearance and the degree of toxicity. The retrospective - prospective study included 42 pediatric patients aged from 0.75 to 17.75 years (median 5.75 years). All patients were threated at the Children and Youth Health Care Institute of Vojvodina (Novi Sad, Serbia), Hemathology and Oncology Section, in the period from June 20 04 to June 2012. 38 examinees diagnosed as acute lymphoblastic leukemia were treated according to two subsequent protocols, ALL IC - BFM 2002 and ALL IC - BFM 2009 of the International BFM study group „I - BFM - SG“ (International Berlin - Frankfurt - Münster Study Group) for management of childhood non - B acute lymphoblastic leukemia. 4 examinees diagnosed as non - Hodgkin lymphoma were treated according to the NHL - BFM 95 protocol. The study included 113 cycles of therapy with methotrexate (1-4 cycles per patient) with 3 86 measured serum concentrations of methotrexate. The range of the applied doses was between 800 and 10,000 mg. The concentration of methotrexate was measured 24, 36 and 42 hours after the initiation of the methotrexate infusion, as well as in longer time intervals when needed. To calculate the pharmacokinetic parameters, the study applied the two - compartment pharmacokinetic model after the termination of intravenous infusion, when relations for pharmacokinetic points existed. Data on clinical and laboratory signs of methotrexate toxicity were collected from medical documentation, and the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, U.S. Department of health and human services, National Institute of Health, National Cancer Institute, was used as the score system for toxicity ranking. In order to determine the effects of the examinees’ characteristics, applied doses and the presence of prolonged elimination on the parameters of interest, three groups of patients were compared (2 g/m2 dose without prolonged elimination, 5 g/m2 without prolonged elimination and 5 g/m2 with prolonged elimination of methotrexate). In the entire group of examinees, the median concentration of methotrexate was 25.82 μmol/l in the 24th hour, 0.68 μmol/l in the 36th hour and 0.24 μmol/l in the 42nd hour of observation. The largest inter - individual variability of methotrexate concentration was observed in the 24th hour while the largest intra - individual variability was recorded in the 36th hour of observation. The median clearance of methotrexate was 8.32l/h. Pharmacokinetic parameters were the following: median volume of the central compartment V1 28.47 l, median constants k10 0,206, k12 0,0245, k21 0,1114, respectively. The strongest influence of the applied dose on the methotrexate concentration was recorded in the 24th hour of observation while no influence on the methotrexate clearance was found. The presence of prolonged elimination of methotrexate causes lower constants k10 and k21. There was no statistically significant interaction between the investigated demographic characteristics (age, body surface and gender) and the methotrexate concentration, nor between the demographic characteristics and the methotrexate clearance. A significant interaction was found between methotrexate concentration and lactat dehydrogenase level, as well as between methotrexate clearance and creatinine and lactate dehydrogenase level, respectively. Most of the observed toxicities were of moderate degree (< 3 degrees). Oral mucositis was the most represented clinical sign of toxicity, and it was of higher degree in the group where the applied dose of methotrexate was higher (5 g/m2 ). Leucopenia and anemia were the most represented laboratory toxic effects. The most severe laboratory signs of toxicity (leucopenia, anemia, increase in AST, ALT and GGT activity) were observed in the group with the higher dose (5 g/m2 ) and prolonged methotrexate elimination. Due to high inter- and intra-individual variability of the drug pharmacokinetics, the basis for the clinical care of patients on high methotrexate dosage therapy is therapeutic drug monitoring – TDM. Routine monitoring of methotrexate serum concentration is important for the identification of patients with a high risk of toxicity, and thus TDM is used as a standard procedure which provides guidelines for leucovorin rescue, particularly for patients with a lower methotrexate clearance or other risks associated with prolonged cytotoxic concent rations (kidney or liver damage, body fluid accumulation in the “third space”, gastrointestinal obstruction). Numerous studies involving pediatric patients have documented the link between a systemic methotrexate exposure on one hand, and the efficiency and toxicity of ethotrexate on the other hand. However, there is no sufficient data on the methotrexate pharmacokinetics in children suffering from acute lymphoblastic leukemia. Moreover, this type of research, involving children treated in the geographical region of this study, have not been conducted.