Sensitive Analysis of Idarubicin in Human Urine and Plasma by Liquid Chromatography with Fluorescence Detection: An Application in Drug Monitoring.

A new approach for the sensitive, robust and rapid determination of idarubicin (IDA) in human plasma and urine samples based on liquid chromatography with fluorescence detection (LC-FL) was developed. Satisfactory chromatographic separation of the analyte after solid-phase extraction (SPE) was performed on a Discovery HS C18 analytical column using a mixture of acetonitrile and 0.1% formic acid in water as the mobile phase in isocratic mode. IDA and daunorubicin hydrochloride used as an internal standard (I.S.) were monitored at the excitation and emission wavelengths of 487 and 547 nm, respectively. The method was validated according to the FDA and ICH guidelines. The linearity was confirmed in the range of 0.1-50 ng/mL and 0.25-200 ng/mL, while the limit of detection (LOD) was 0.05 and 0.125 ng/mL in plasma and urine samples, respectively. The developed LC-FL method was successfully applied for drug determinations in human plasma and urine after oral administration of IDA at a dose of 10 mg to a patient with highly advanced alveolar rhabdomyosarcoma (RMA). Moreover, the potential exposure to IDA present in both fluids for healthcare workers and the caregivers of patients has been evaluated. The present LC-FL method can be a useful tool in pharmacokinetic and clinical investigations, in the monitoring of chemotherapy containing IDA, as well as for sensitive and reliable IDA quantitation in biological fluids.

Carbon-based ruthenium nanomaterial-based electroanalytical sensors for the detection of anticancer drug Idarubicin.

In this work, a novel nanosensing platform was suggested based on ruthenium for the sensitive determination of Idarubicin anticancer drugs. Ruthenium/Vulcan carbon-based nanoparticles were synthesized ultrasonication method and then characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD). The mean particle size of the nanoparticles calculated by the TEM analysis was found to be 1.98 nm ± 0.29 nm, and the Ru nanoparticles were mostly dispersed on the support material. Glassy carbon electrode (GCE) surface was modified with Ruthenium/Vulcan carbon-based nanomaterials (Ru@VC), and characterization of the nanosensor was performed using electrochemical impedance spectroscopy and cyclic voltammetry. The limit of detection (LOD) and limit of quantification (LOQ) values were found as 9.25 × 10-9 M and 2.8 × 10-8 M in buffer samples. To demonstrate the applicability and validity of developed nanosensor, it was used for the determination of Idarubicin in Idamen® IV (10 mg/10 mL vial) and human serum sample. The results of recovery studies showed that the Ru@VC/GCE nanosensor was free from excipient interferences in the dosage forms of injection, and it can be successfully applied to biological samples.

Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial.

BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.

Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML).

Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

HPLC quantification of doxorubicin in plasma and tissues of rats treated with doxorubicin loaded poly(alkylcyanoacrylate) nanoparticles.

The long-term clinical use of doxorubicin (Dox), one of the most important anticancer agent in use, is limited by dose-related acute cardiotoxicity, myelo-suppression and multidrug resistance developed by cancer cells. To improve the antitumor efficacy and reduce the toxicity of Dox, many drug delivery systems have been developed, including poly(alkylcyanoacrylate) (PACA) nanoparticles. A new formulation of PACA nanoparticles with potential stealth properties were prepared by redox radical emulsion polymerization and associated to Dox in our laboratory. To comparatively investigate the pharmacokinetics and the biodistribution of different formulations of Dox associated PACA nanoparticles, a simple and rapid high performance liquid chromatographic method (HPLC) was developed for the quantification of Dox in plasma and tissues of rats treated with Dox loaded PACA nanoparticle (Dox-PACA). Dox was eluted at 4.4 min and it was well separated from its main metabolites doxorubicinol (Doxl) and doxorubicinon (Doxon) and idarubicin (Ida) used as internal standard (IS). Extraction of Dox from biological media was achieved by liquid-liquid extraction. The recovery of total Dox (i.e. free Dox and Dox associated with nanoparticles) from plasma and tissues (liver, spleen and heart) spiked with Dox-PACA were 71 and 78% for 0.05 and 1 µg/mL in rat plasma, respectively, and 73% and 80% for 0.5 and 10 µg/g in tissues, respectively. The method is linear from 0.05 to 1.5 µg/mL of Dox in plasma. The limit of detection of the method is 0.5 ng of Dox per injection (50 µL). The between-day and within-day precisions of the method were 97.1-102.9% and 97.3-101.7% for concentrations ranging from 0.05 to 1 µg/mL, respectively. Preliminary data suggested that this method can be applied to determine the pharmacokinetic and biodistribution of Dox associated with PACA nanoparticles after intravenous administration to rats.

The encapsulation of idarubicin within liposomes using the novel EDTA ion gradient method ensures improved drug retention in vitro and in vivo.

The purpose of this study was to design a new stable liposomal formulation for the anticancer drug idarubicin. Idarubicin is a relatively hydrophobic member of the anthracycline family. It exhibits pronounced bilayer interactions leading to rapid in vivo drug release from liposomes. This rapid drug leakage is due to the presence of cholesterol and charged lipids in the liposomal bilayer. Therefore, a novel method of remote drug loading was developed to prevent rapid drug release from PEGylated cholesterol-containing liposomes. This method uses EDTA disodium or diammonium salt as an agent to form low solubility complexes between the drug and EDTA molecules inside the liposomes, thus yielding improved drug retention. The efficiency of idarubicin encapsulation is close to 98% at a drug to lipid molar ratio of 1:5. An in vitro long-term storage experiment confirmed the high stability of the liposomes. The in vivo studies also showed the superiority of the new idarubicin formulation over the recently used remote loading methods. The plasma level of idarubicin was much higher when EDTA liposomes were used. The presented results fully demonstrate the superiority of the proposed method of idarubicin encapsulation over existing methods. The method offers the possibility of encapsulating not only all the anthracyclines, but also other weakly amphiphilic bases within the liposomes.

A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia.

Histone deacetylase inhibitors (HDACi) affect chromatin remodelling and modulate the expression of aberrantly silenced genes. HDACi have single-agent clinical activity in haematological malignancies and have synergistic anti-leukaemia activity when combined with anthracyclines in vitro. We conducted a two-arm, parallel Phase I trial to investigate two schedules of escalating doses of vorinostat (Schedule A: thrice daily (TID) for 14 d; B: TID for 3 d) in combination with a fixed dose of idarubicin in patients with refractory leukaemia. Of the 41 patients enrolled, 90% had acute myeloid leukaemia, with a median of 3 prior therapies. Seven responses (17%) were documented (two complete response (5%), one complete response without platelet recovery (2.5%), and four marrow responses). The 3-d schedule of vorinostat was better tolerated than the 14-d schedule. The maximum tolerated dose for vorinostat was defined as 400 mg TID for 3 d. The most common grade 3 and 4 toxicities included mucositis, fatigue and diarrhoea. Correlative studies demonstrated histone acetylation in patients on therapy and modulation of CDKN1A and TOP2A (topoisomerase II) gene expression. Pharmacokinetic analysis confirmed a dose-related elevation in plasma vorinostat concentrations. The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting.

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response.

AIMS: To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment. METHODS: Mononuclear blood cells from AML patients were isolated before (n = 20) and after anthracycline infusion (n = 24). The pre-treated cells were incubated in vitro with daunorubicin (DNR) and/or idarubicin (IDA). Anthracycline concentrations were determined by high-performance liquid chromatography, and apoptosis was detected by propidium iodine staining using a flow cytometer. RESULTS: There was a clear concentration-response relationship between intracellular anthracycline levels and apoptosis albeit with a large interindividual variation. Intracellular levels >1200 muM always led to high apoptosis development (>60%) in vitro. The intracellular concentrations of DNR in vivo (n = 24) were more than tenfold lower than the concentrations needed to induce effective apoptosis in vitro, although a significant relation between in vivo concentrations and clinical remission was found. We also found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and clinical remission. CONCLUSIONS: Our results indicate that intracellular anthracycline levels in vivo are suboptimal and that protocols should be used that increase intracellular anthracycline levels.

Increased myelotoxicity of idarubicin: is there a pharmacological basis? Results of a pharmacokinetic and an in vitro cytotoxicity study.

BACKGROUND: Clinical trials evaluating idarubicin (IDA) in acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma (NHL) have provided some evidence for an increased myelotoxicity of IDA compared to other anthracyclines. IDA is known to be less sensitive towards multidrug resistance mediated by P-glycoprotein (P-gp). This phenotype is a major impediment to successful antineoplastic treatment, but P-gp is also expressed on hematopoietic stem cells (HSC). METHODS: We investigated the pharmacokinetics of IDA and etoposide (ETO) in seven previously untreated patients with aggressive NHL. The patients received a CHOP-derived protocol (CIVEP) in which doxorubicin (DOX) was substituted by IDA 11-16 mg/m(2) and ETO 3 x 100 mg/m(2) was added. Furthermore, we evaluated in vitro the impact of P-gp expression on the cytotoxicity of DOX and IDA in cells from three parental chemosensitive leukemia and lymphoma cell lines (HL60, U937, CCRF) and their resistant sublines, as well as in CD34-positive HSC. RESULTS: The peak plasma levels (C(max)), terminal elimination half-life (t(1/2)) and area under the concentration curve (AUC) both for IDA and for ETO did not differ from published data. In cell line models the numbers of viable cells in a P-gp-expressing resistant CCRF-VCR100 subline were significantly more reduced by IDA ( P<0.001), but there was no difference in the cytotoxicities of IDA and DOX in chemosensitive CCRF cells and in the (non-P-gp-expressing) resistant U937 and HL60 sublines. Cytotoxicity against HSC was more pronounced after incubation with IDA than after treatment with DOX ( P=0.014), even when a tenfold higher concentration of DOX than of IDA was used. The addition of cyclosporin A increased the cytotoxic effect of DOX but not that of IDA in HSC. CONCLUSIONS: The pharmacokinetics of IDA and its main metabolite idarubicinol in CHOP-derived protocols were not different from data obtained with other combinations or monotherapy. The increased myelotoxicity of IDA may be a consequence of P-gp expression in CD34-positive HSC.

Improved retention of idarubicin after intravenous injection obtained for cholesterol-free liposomes.

To date there has been a focus on the application of sterically stabilized liposomes, composed of saturated diacylphospholipid, polyethylene glycol (PEG) conjugated lipids (5-10 mole%) and cholesterol (CH) (>30 mole%), for the systemic delivery of drugs. However, we are now exploring the utility of liposome formulations composed of diacylphospholipid conjugated PEG mixtures prepared in the absence of added cholesterol, with the primary objective of developing formulations that retain encapsulated drug better than comparable formulations prepared with cholesterol. In this report the stability of cholesterol-free distearoylphosphatidylcholine (DSPC):distearoylphosphatidylethanolamine (DSPE)-PEG(2000) (95:5 mol/mol) liposomes was characterized in comparison to cholesterol-containing formulations DSPC:CH (55:45 mol/mol) and DSPC:CH:DSPE-PEG(2000) (50:45:5 mol/mol/mol), in vivo. Circulation longevity of these formulations was determined in consideration of variables that included varying phospholipid acyl chain length, PEG content and molecular weight. The application of cholesterol-free liposomes as carriers for the hydrophobic anthracycline antibiotic, idarubicin (IDA), was assessed. IDA was encapsulated using a transmembrane pH gradient driven process. To determine stability in vivo, pharmacokinetic studies were performed using 'empty' and drug-loaded [(3)H]cholesteryl hexadecyl ether radiolabeled liposomes administered intravenously to Balb/c mice. Inclusion of 5 mole% of DSPE-PEG(2000) or 45 mole% cholesterol to DSPC liposomes increased the mean plasma area under the curve (AUC(0-24h)) 19-fold and 10-fold, respectively. Cryo-transmission electron micrographs of IDA loaded liposomes indicated that the drug formed a precipitate within liposomes. The mean AUC(0-4h) for free IDA was 0.030 micromole h/ml as compared to 1.38 micromole h/ml determined for the DSPC:DSPE-PEG(2000) formulation, a 45-fold increase, demonstrating that IDA was retained better in cholesterol-free compared to cholesterol-containing liposomes.

A pharmacokinetic study of idarubicin in Japanese patients with malignant lymphoma: relationship with leukocytopenia and neutropenia.

To clarify the pharmacokinetic properties of idarubicin (IDA) in Japanese patients and to clarify the relationship between the pharmacokinetic parameters of IDA or idarubicinol (IDAol), an active metabolite of IDA, and leukocytopenia or neutropenia, we examined the pharmacokinetics of IDA in patients with malignant lymphoma. Nine of 21 patients registered in an early phase II study of IDA were enrolled in the pharmacokinetic study. IDA (12 or 15 mg/m2) was administered by intravenous infusion for 5 minutes. The elimination half lives (t 1/2) of IDA were 11.0 hours and 12.5 hours after administration of 12 and 15 mg/m2 IDA, respectively. IDAol appeared rapidly both in plasma and in blood cells, and its concentrations exceeded those of IDA within 4 hours. IDAol had a very long t 1/2 (69.2 hours and 70.0 hours for 12 and 15 mg/m2, respectively). The areas under the concentration curves of IDAol in plasma were 3.4 and 5.8 times higher than those of IDA after administration of 12 and 15 mg/m2 IDA, respectively. The t 1/2 of IDAol in plasma correlated significantly with the nadir of neutrophils, and the steady-state volume of distribution of IDA in plasma and in blood cells correlated significantly with the nadirs of white blood cells and neutrophils. These results suggest that both IDA and IDAol play an important role in leukocytopenia or neutropenia. No substantial differences between Japanese and Caucasian people in the pharmacokinetics of IDA were apparent.

Simultaneous determination of doxorubicin, daunorubicin, and idarubicin by capillary electrophoresis with laser-induced fluorescence detection.

The separation and simultaneous determination of doxorubicin, daunorubicin and idarubicin was investigated using capillary electrophoresis with laser-induced fluorescence detection. Because the three anthracycline antibiotics were similar in structure and mass, careful manipulation of the electroosmotic flow and electrophoretic mobilities was required. A buffer consisting of 100 mM borate, adjusted to pH 9.5, containing 30% acetonitrile was found to provide a very efficient and stable electrophoretic system for the analysis of the three anthracyclines. The method was applied to the determination of three anthracyclines in serum samples. Responses were linear in the range of 10-500 ng.mL-1 and the detection limits were lower than 0.9 ng.mL-1.

Induction of apoptosis by idarubicin: how important is the plasma peak?

OBJECTIVES: It is still not clear whether a high plasma peak or a prolonged plasma presence of the drug is optimal for chemotherapy with anthracyclines. A high plasma peak seems to correlate with the liberation of oxygen radicals and cumulative delayed cardiotoxicity, and therefore, should be avoided. On the other hand, its role in attaining the desired therapeutic effect, i.e. induction of apoptosis in tumor cells, has not been clearly elucidated. METHODS: Idarubicin is the only anthracycline that can be applied orally. We measured the DNA-binding of idarubicin and idarubicinol and the induced apoptosis in the human promyelocytic HL-60 leukemia cell line. Various pharmacokinetic profiles, with and without clinically relevant peak concentrations, were simulated in vitro. RESULTS: The concentration necessary for maximal DNA-binding and subsequent induction of apoptosis was 1.5 microg/ml for 20 minutes which is well above the plasma concentration achievable in therapy. A plateau of apoptosis was observed after 90 minutes of incubation; a prolongation above 90 minutes did not increase the rate of apoptosis. We simulated a bolus application and a continuous infusion using two different pharmacokinetic profiles of idarubicin with comparable AUCs (area under the time curve). After 48 hours of total incubation, the viability of HL-60 cells was 56.88% with profile 1 (50 ng/ml idarubicin for 2 hours) and 83.00% with profile 2 (4.25 ng/ml for 24 hours). CONCLUSIONS: Although these in vitro experiments are not directly applicable to the clinical situation, they do indicate that a prolongation of the application time up to at least 90 minutes, either by continuous infusion or by oral application, may be acceptable as a method of increasing apoptosis. On the other hand, the plasma peak seems to be an important factor for the induction of apoptosis. Further studies are in progress to define the minimal plasma peak necessary to induce a maximum of apoptosis.

Determination of idarubicin and idarubicinol in rat plasma using reversed-phase high-performance liquid chromatography and fluorescence detection.

A reversed-phase high-performance liquid chromatographic method is described for the simultaneous determination of idarubicin and idarubicinol in rat plasma. Blood samples were analyzed from 16 rats which had received an intravascular dose of 2.25 mg kg(-1) idarubicin. After deproteinization with acetonitrile, the separation was performed with a LiChrospher 100 RP-18 column (5 microm), using fluorescence detection (excitation: 485 nm/emission: 542 nm). The mean recovery was 95.6% for idarubicin and 90.7% for idarubicinol, respectively. The detection limit was 0.25 ng ml(-1) using an injection volume of 50 microl. Daily relative standard deviation (RSD) was 3.2% (10 ng idarubicin/ml, n=10) and 4.4% (10 ng idarubicinol/ml, n=10).

An improved HPLC method for therapeutic drug monitoring of daunorubicin, idarubicin, doxorubicin, epirubicin, and their 13-dihydro metabolites in human plasma.

A single high-performance liquid chromatography (HPLC) method, suitable for the analysis of daunorubicin, idarubicin, doxorubicin, epirubicin, and their 13-dihydro metabolites is validated in the present study. Preparation of plasma samples was performed by a first extraction of analytes with a chloroform/1-heptanol mixture (9:1) and reextraction with ortophosphoric acid 0.1 M. The chromatographic analysis was carried out by reversed-phase isocratic elution of anthracyclines with a Supelcosil LC-CN 5 mm column (25 cm x 4.6 mm internal diameter; Supelco) and detection was accomplished by spectrofluorimetry at excitation and emission wavelengths of 480 and 560 nm, respectively. All anthracyclines eluted within 15 minutes of injection and the method appeared to be specific, because the chromatographic assay did not show interferences at the retention time of analytes. The linearity, evaluated over a concentration range of 0.4-10,000 ng/mL, gave regression coefficients better than 0.999, with recoveries of doxorubicin-doxorubicinol and epirubicin-epirubicinol of 67%-109% and 61%-109% respectively, and 93%-109% for the other compounds. The limits of detection and quantification were 0.4 ng/mL in a 50-mL sample (40 pg/injection) for all anthracyclines tested. The method proved to be precise and accurate, as the within-day and between-day coefficients of variation were less than 10% and the accuracy of the assay was in the range of 91%-107%. Overall results indicate that it is feasible to analyze all the anthracyclines used in clinical practice and their major metabolites with a single optimized method, thereby simplifying their monitoring in chemotherapeutic regimens of cancer patients.

Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model.

PURPOSE: Idarubicin (4-demethoxy-daunorubicin) is more potent and less cardiotoxic than the commonly used anthracyclines, doxorubicin and daunorubicin. In addition, idarubicin is metabolized to an active metabolite, idarubicinol, in contrast to other anthracyclines whose alcohol metabolites are much less active than the parent drug. The current study was performed in nonhuman primates to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics of idarubicin and idarubicinol and to compare them to the pharmacokinetics of daunorubicin and daunorubicinol. METHODS: A dose of 30 mg/m2 of daunorubicin or 8 mg/m2 of idarubicin was administered intravenously over 15 minutes. Plasma and CSF were sampled frequently from the end of the infusion to 72 to 96 hours after infusion. Drug and metabolite concentrations were measured using high-pressure liquid chromatography (HPLC). RESULTS: Daunorubicin elimination from plasma was triphasic with a terminal half-life of 5.9 +/- 1.8 hours, area under the concentration-time curve (AUC) 22.5 +/- 9.2 mumol/L.min, and clearance 2790 +/- 960 mL/min/m2. Daunorubicinol elimination was biphasic with a terminal half-life 10.2 +/- 2.3 hours and an AUC 74.5 +/- 5.3 mumol/L.min. Idarubicin elimination was triphasic with terminal half-life of 12.3 +/- 11.4 hours, a AUC 10.8 +/- 3.7 mumol/L.min, and clearance 1650 +/- 610 mL/min/m2. Idarubicinol elimination was biphasic with a terminal half-life 28.7 +/- 4.2 hours and AUC 67 +/- 9.8 mumol/L.min. CSF penetration was low for both parent drugs and their metabolites. CSF idarubicin was measurable at a single time point (1 hour after administration) for 2 animals, and was not measurable for the third. The CSF to plasma concentration ratio at that time point was 8% in 1 animal and 15% in the other. Idarubicinol was detected in 2 to 4 samples at various times, appearing as early as 1 hour in 1 animal and persisting as late as 48 hours in another. The CSF to plasma concentration ratio at corresponding time points was 1.9 +/- 0.6%. Daunorubicin was measurable for < 6 hours after intravenous administration. For individual animals, the mean CSF to plasma concentration ranged from 4% to 12%. Daunorubicinol was detectable by 1 hour in 2 of 3 animals and by 3 hours in the other, and remained detectable at 24 hours in 2 of 3. The terminal half-life of daunorubicinol in CSF was 8.8 +/- 1.3 hours, the AUC was 1.8 +/- 1.5 mumol/L.min, and the AUCCSF to AUCplasma ratio was 2.4 +/- 1.9%. CONCLUSION: Idarubicin, idarubicinol, daunorubicin, and daunorubicinol penetrate poorly into the CSF after intravenous administration.

Determination of idarubicin and idarubicinol in plasma by capillary electrophoresis.

A rapid and sensitive capillary electrophoretic method for the determination of idarubicin and its metabolite idarubicinol in plasma has been developed and validated. Plasma is extracted by liquid-liquid extraction using chloroform. Idarubicin, idarubicinol and the internal standard daunorubicin can be separated in less than 5 min using a phosphate buffer of pH 5 with 70% acetonitrile. Laser-induced fluorescence detection with an Ar ion laser operated at 488 nm provides a sensitive and selective detection method without interferences from biological fluids. The small sample volume of 100 microl is of particular advantage for studies in pediatric oncology. The reproducibility of the method has been shown to be sufficient for drug monitoring or pharmacokinetic studies. The limit of quantification for idarubicin in plasma is 0.5 ng/ml.

A phase-II study with idarubicin, ifosfamide and VP-16 (IIVP-16) in patients with refractory or relapsed aggressive and high grade non-Hodgkin's lymphoma.

We report a phase-II study of idarubicin, ifosphamide and etoposide (IIVP-16) in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. The IIVP-16 regimen consisted of idarubicin (10 mg/m2 i.v. days 1 + 2 or days 1 + 8), ifosfamide (1000 mg/m2 i.v. days 1-5) and VP-16 (150 mg/m2 i.v. days 103). 40 patients were enrolled. Of 38 evaluable patients, 26 had centroblastic subtype, followed by lymphoblastic (6), immunoblastic (2), and other entities (4). 18 patients were primary resistant; 14 patients had early relapse (CR less than 12 months) and 8 patients late relapse (CR longer than 12 months). The median number of different prior chemotherapy regimens was 2 (range 1 to 6). 20 patients had received additional radiotherapy. The response-rate was 47.4% including 8 CR (21.1%) and 10 PR (26.3%). IIVP-16 was more effective in patients with relapsed disease when compared with patients with primary resistant disease (response rate 65% vs. 27.8%, p < 0.025). Leukopenia and thrombocytopenia were the major toxicities occurring in 73/107 (68.2%) and 57/107 (53.3%) of cycles (WHO grade IV). IIVP-16 is an effective regimen particularly in patients with unfavorable relapsed NHL.

Plasma pharmacokinetics of idarubicin and its 13-dihydro metabolite--a comparison of bolus versus 2 h infusion during a 3 day course.

The plasma pharmacokinetics of a second generation anthracycline derivative, idarubicin (Ida), have been studied in 17 patients with acute myelocytic leukemia (AML) and high risk features. The drug (10 mg/m2) was given in a randomized cross-over design as 3 min and 2 h infusions for three consecutive days. Cytosine arabinoside (Ara-C, 1 g/m2) was given on days 1-4. The plasma concentration time course of Ida was most properly described by the three-compartment pharmacokinetic model, independent of administration time. The maximum plasma concentration (Cmax) of Ida was reduced by a factor of 3 by increasing the infusion time from 3 min to 2 h. The pharmacokinetic pattern of the active metabolite idarubicinol (IdaOH) was only to a minor extent affected by the longer infusion time. The time course of IdaOH following each dose of Ida was accurately described by the one-compartment model with a first-order formation phase. The are under the plasma concentration versus time curves (AUC) of Ida and IdaOH were not affected by the administration time. Following Ida in combination with Ara-C, the medial duration of leukopenia (< 1.0 x 10(9)/l) was 14 days (range 5-56) and of thrombocytopenia (< 50 x 10(9)/l) was 22 days (range 7-120). The large majority of patients developed infectious complications. Two patients with MDS-AML showed a good response. The results of the present study give no evidence of reduced hematologic toxicity by increasing the administration time of Ida from 3 min to 2 h. However, minimizing Cmax, by administration of Ida as prolonged infusion during a 3 day course, might be clinically important in order to reduce cardiotoxicity and hopefully to increase anti-tumor efficacy through an increased accumulation of Ida and IdaOH in leukemic cells.

Attenuated-dose idarubicin in acute myeloid leukaemia of the elderly: pharmacokinetic study and clinical results.

AML in the elderly is characterized by intrinsic biological features implying an enhanced chemoresistance. Intensive chemotherapy should be the treatment of choice, but the standard doses could induce unacceptable rates of aplastic deaths. We evaluated the efficacy of an induction protocol with attenuated-dose idarubicin (IDA) 8 mg/m2 for 3 d plus cytarabine and etoposide in 26 AML patients aged > 60. 18 patients (69%) achieved CR, five (19%) were non-responders and three (12%) died during induction. To compare the pharmacokinetics of IDA between elderly and young patients, we assayed daily the serum level of the drug and of its metabolite (idarubicinol, IDAol) in a group of eight elderly patients who received a dose of 8 mg/m2 (group A) and in a group of nine younger AML patients treated with 12 mg/m2 (group B). The apparent terminal half-life of IDAol was significantly longer in the elderly than in the younger patients (mean half-life 59.7 h versus 41.4 h, P < 0.05). The values of the area under the serum concentration curve of IDAol indicated that the two patient groups received a very similar exposure to the drug despite the different doses. In conclusion, this protocol, based on attenuated doses of IDA, compares well with the results obtained previously in similar age-matched patient series.