daunorubicinol and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

There is an extreme paucity of pharmacokinetic data for anticancer agents in infants. Therefore, we aimed at characterizing the pharmacokinetics for daunorubicin in infants and examined their relationship to age, body weight, and body surface area.. Leukemia patients treated according to the Interfant 99 protocol received 30 mg/m(2) daunorubicin, with dose reduction to 3/4 for patients 6-12 months old and 2/3 for patients <6 months, respectively. Plasma samples from 21 patients (aged 0.05-1.88 years) were collected and analyzed for daunorubicin and daunorubicinol. Samples from 12 children (age 1.6-18.8 years), who received daunorubicin in an earlier investigation, were used for pharmacokinetic model building using the software NONMEM.. Plasma concentration time profiles could be described using a two compartment model. Daunorubicin clearance was 43.9 L hr(-1) m(-2) +/- 65% and central volume of distribution 16.4 L m(-2) +/- 46%, whereas apparent clearance of daunorubicinol was 19.1 L hr(-1) m(-2) +/- 32% and apparent volume of distribution 228 L m(-2) +/- 80% (mean +/- interindividual variability). No age-dependency in any of the BSA-normalized pharmacokinetic parameters was observed. Consequently, due to the empirical dose reduction in infants the overall exposure to daunorubicinol in infants was smaller than would be expected from older children. Patients aged <6 months experienced more infections in the induction phase than the group aged 6-12 months at diagnosis. Other toxicities were similar in both groups.. We observed no indication of an age-dependency in the pharmacokinetics of daunorubicin. Pediatr Blood Cancer 2010;54:355-360.

Topics: Adolescent; Age Factors; Antibiotics, Antineoplastic; Child; Child, Preschool; Daunorubicin; Female; Humans; Infant; Infant, Newborn; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The pharmacokinetics of DaunoXome were studied during a multicentric phase I-II study performed in children suffering from relapsed acute lymphoblastic leukaemia and treated on a weekly schedule.. A group of 18 patients were studied during the first course of treatment at dose levels between 40 and 120 mg/m2. Blood samples were obtained up to 72 h after infusion. The liposomal and free forms of daunorubicin, as well as daunorubicinol, were separated and quantified by HPLC using fluorometric detection, and data were analysed using a model-independent approach.. Unchanged liposomal daunorubicin disappeared from plasma following a monoexponential decay. Its AUC represented 95.8% of the total fluorescent species found in plasma and increased linearly with the dose administered. The elimination half-life was 5.23 h, total plasma clearance 0.344 1/h per m2, and volume of distribution at steady state 2.08 l/m2. Free daunorubicin and daunorubicinol were detected in plasma at all time-points studied. Their AUCs represented, respectively, 2.53% and 1.70% of total fluorescent species and their elimination half-lives were, respectively, 16.6 h and 22.3 h. The daunorubicinol/daunorubicin AUC ratio was 0.82%.. This study is the first to demonstrate that free daunorubicin is present in plasma after DaunoXome administration and that it originates from in vivo release from the liposomes. The pharmacokinetics of free daunorubicin appeared to be comparable to those observed after conventional administration. However, the concentration of daunorubicinol appeared to be lower than that found after conventional administration of daunorubicin.

Topics: Adolescent; Antibiotics, Antineoplastic; Child; Child, Preschool; Daunorubicin; Drug Carriers; Female; Half-Life; Humans; Liposomes; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Time Factors

The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.

Topics: Acute Disease; Adolescent; Adult; Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carrier Proteins; Daunorubicin; Female; Humans; Leukemia, Myeloid; Male; Membrane Glycoproteins; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol

Topics: 20-Hydroxysteroid Dehydrogenases; Adipocytes; Alcohol Oxidoreductases; Aldehyde Reductase; Aldo-Keto Reductase Family 1 Member C3; Cell Line, Tumor; Daunorubicin; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Hydroxysteroid Dehydrogenases; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Microenvironment

We report the first known case of daunorubicin administered directly into the human central nervous system. A 3 1/2-year-old female with pneumonia and otitis media was diagnosed with acute lymphoblastic leukemia and was admitted for antibiotics and chemotherapy. On the first day she inadvertently received a 17 mg intrathecal (IT) injection of daunorubicin. When the error was recognized about 1 hour later, her cerebrospinal fluid (CSF) was exchanged with sterile saline by barbotage, IT hydrocortisone was given, a subarachnoid catheter was inserted, and the CSF was allowed to drain for 36 hours. Only 5.6 mg (33%) of the dose was recovered from CSF, 2.7 mg as daunorubicin and 2.9 mg as the metabolite, daunorubicinol. Initially she was asymptomatic and induction therapy continued with vincristine, 1-asparaginase, prednisone, and IT methotrexate. One week after the daunorubicin injection she developed headache and irritability; CSF protein was 3.2 gm/dl. On the 12th day, she developed fungal sepsis and worsening pneumonia. On the 15th day, she became comatose with a flacid paraparesis, areflexia, and an ascending progressive bulbar palsy. A series of computerized tomography scans over 6 weeks showed increasing diffuse cerebral atrophy. Nerve conduction velocity studies were consistent with an axonal neuropathy. Despite her multiple concurrent medical problems, the timing and characteristics of neurologic damage suggest that IT daunorubicin caused progressive destruction of the nervous system.

Topics: Central Nervous System Diseases; Child, Preschool; Daunorubicin; Female; Humans; Injections, Spinal; Precursor Cell Lymphoblastic Leukemia-Lymphoma