Pharmacokinetics Of Mitoxantrone Research Articles

Effects of the isoflavonoid biochanin A on the transport of mitoxantrone in vitro and in vivo

The aim of our study was to investigate the effect of biochanin A on the accumulation and transport of mitoxantrone in breast cancer resistance protein (BCRP)-expressing normal cells and its impact on the pharmacokinetics (PK) and tissue distribution of mitoxantrone. In accumulation studies, the intracellular level of mitoxantrone was significantly increased in the presence of 2.5 or 25 microM of biochanin A in both murine and human BCRP-expressing Madin-Darby canine kidney (MDCK) cells, with no effect in corresponding MDCK/Mock cells. In bi-directional transport studies, the P(app,B-A) value of mitoxantrone with biochanin A co-treatment was much lower (6.66+/-0.84x10(-7) cm/s) than that in the absence of biochanin A (21.4+/-4.14x10(-7) cm/s), indicating inhibition of Bcrp1-mediated efflux. To evaluate whether our in vitro results might translate into an in vivo interaction, mitoxantrone PK and tissue distribution, with and without co-administration of biochanin A, was investigated. In contrast to our in vitro results, biochanin A (10 mg/kg, i.v.) had no impact on the concentration of mitoxantrone in plasma and most tissues collected (brain, heart, liver and lung). Surprisingly, the concentrations of mitoxantrone in spleen and kidney were even decreased when biochanin A was co-administered. Interestingly, it was found that the intracellular fluorescence of mitoxantrone was decreased 31.9% when co-incubated with 10 microM biochanin A in P-glycoprotein (P-gp) expressing MCF-7/ADR cells, indicating potential P-gp stimulation. The species difference of the inhibitory effect of biochanin A on BCRP, the extensive metabolism of biochanin A, as well as the stimulation effect of biochanin A on P-gp, may contribute to this in vitro-in vivo disconnect.

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia.

Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.

Pharmacokinetics of mitoxantrone, etoposide and cytosine arabinoside in leukemic cells during treatment of acute myelogenous leukemia—Relationship to treatment outcome and bone marrow toxicity

Twenty-seven patients with acute myelogenous leukemia (AML) were given remission induction treatment with mitoxantrone, etoposide and cytosine arabinoside (ara-C). The pharmacokinetics in leukemic blood cells of mitoxantrone, etoposide and the active metabolite of ara-C, ara-CTP, were determined during the first day of treatment. There was a large interpatient variability of the area under the time versus concentration curve (AUC) for all three drugs. On the individual level, there was no correlation between the AUCs of the different drugs. Neither did the AUC of any individual drug nor the calculated total intracellular drug exposure have any association with the outcome of treatment or hematological toxicity, measured as duration of leukopenia/thrombocytopenia. In conclusion, when combination chemotherapy with mitoxantrone, etoposide and ara-C is given to patients with AML, intracellular drug concentrations, achieved after the first dose of each drug, do not seem to be predictive for treatment response or hematological toxicity.

Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone. A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro. We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma. This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

Clinical pharmacokinetics of mitoxantrone after intraperitoneal administration.

The pharmacokinetics of intraperitoneally (i.p.) injected mitoxantrone was determined in plasma and peritoneal dialysate taken from five patients presenting with cancer confined to the peritoneal cavity over a sampling period of 1 week. The drug was given through a Tenckhoff catheter as a 15-min infusion and the peritoneal dialysate was removed after a dwell time of 4 h; the doses delivered varied between 20 and 50 mg/m2. Dose-limiting local toxicity was moderate. The HPLC technique used for mitoxantrone determinations proved to be sensitive within the range of 0.3-4,000 ng/ml. Median values obtained for the pharmacokinetic parameters of mitoxantrone in peritoneal dialysate were: t1/2 beta (distribution), 56.4 min (range, 16.8-235.8 min); t1/2 gamma (elimination), 128 h (range, 28.3-171.0 h); Vdss (volume of distribution at steady state), 24.8 l (range, 17.0-232.5 l); delta'ss (volume of distribution at steady state corrected for the body surface area in square meters), 14.4 l/m2 (range, 10.6-129.2 l/m2); and clearance, 0.25 l/h (range, 0.16-0.59 l/h). For plasma the median values were: t1/2 alpha (absorption), 58.8 min (range, 45.6-87.0 min); t1/2 beta (distribution), 2.5 h (range, 1.4-6.3 h); t1/2 gamma (elimination), 44.1 h (range, 9.1-91 h); Vdss, 2,152 l (range, 352-19,733 l); delta'ss, 1,345 l/m2 (range, 220-11,606 l/m2); and clearance, 117 l/h (range, 51-1,609 l/h). After 168 h the median plasma concentration was 1 ng/ml. The median peak concentration in peritoneal dialysate was 490 ng/ml. Considering the moderate toxicity observed and the concentrations achieved in the peritoneal dialysate, removal of the dialysate after certain dwell times seems reasonable to be a reasonable approach for the optimization of i.p. treatment with mitoxantrone.

Pharmacokinetics of Mitoxantrone in Plasma and Leukemic Cells During Treatment of Patients with Acute Non-Lymphocytic Leukemia

The pharmacokinetics of mitoxantrone was studied in the plasma and peripheral leukemic cells in 14 patients receiving induction treatment for acute non-lymphocytic leukemia. The disappearance of mitoxantrone from plasma was biphasic with a mean distribution half life of 10.4 minutes and a mean elimination half life of 17.1 hours. At the end of the infusion, the mean mitoxantrone concentration in leukemic cells was 9.6 times (range 2.1-22.7) higher than in plasma and remained relatively stable in the cells until the next infusion following 24 hours after the first. The area under the concentration-time curve (AUC0-20h) in leukemic cells was 23-191 times larger than the AUC0-α in plasma. In the individual patient there was no correlation between the AUC in leukemic cells and AUC in plasma. Since mitoxantrone acts intracellularly, concentrations in the leukemic cells might predict the antileukemic effect better than plasma concentrations.

Quantification of mitoxantrone in bone marrow by high-performance liquid chromatography with electrochemical detection

An analytical method for the determination of mitoxantrone in bone marrow was developed using high-performance liquid chromatography with electrochemical detection. The extraction procedure was optimized by investigating several factors which potentially could influence the recovery of mitoxantrone from bone marrow cells. The mean recovery of mitoxantrone from rat bone marrow was found to be 81.7% with a coefficient of variation 3.8%. High-performance liquid chromatography was carried out to quantitate mitoxantrone using ametantrone as internal standard. The detection limit of our analytical method amounts to 100 pg on-column, corresponding to 1 ng/ml of cell suspension containing 2 x 10(7) cells and a day-to-day variation of maximally 8%. Storage of bone marrow samples, containing mitoxantrone, for one to fourteen days resulted in a mean recovery of 94%, as compared to freshly analysed samples. Subsequently we studied the pharmacokinetics of mitoxantrone in rat bone marrow. It appeared that after an intravenous bolus injection of mitoxantrone (2.5 mg/kg) in rats, the drug accumulated in the femoral bone marrow for about four days, and thereafter gradually declined.

Pharmacokinetics of mitoxantrone in patients after 2 h and 24 h intra-arterial administration

The pharmacokinetic parameters of mitoxantrone in patients with liver metastasis after intra-arterial 2 h and 24 h infusion (dosage 12 mg/m2) were investigated. Peak plasma concentrations were 305 +/- 60 ng/ml at 2 h infusion and 244 +/- 89 ng/ml at 24 h infusion. These peak plasma concentrations occurred at 0.9 +/- 0.8 h during 2 h infusion and 5.5 +/- 3.4 h during 24 h infusion. No significant difference between both intra-arterial administrations in elimination half-life (50-223 h at 2 h infusion, 58-246 h at 24 h infusion) and area under the plasma concentration-time curve (AUC0-72 = 11.6 micrograms/ml.h for 2 h infusion, AUC0-72 = 11.2 micrograms/ml.h for 24 h infusion) could be found. The results indicate that no change of availability in the central compartment at infusion of mitoxantrone over a period of 24 h could be achieved. The 2 h infusion lead to sufficient plasma levels with pharmacokinetic parameters of mitoxantrone similar to 24 h infusion and showed a good clinical picture with mild toxicity.

Novel assay method for mitoxantrone in plasma, and its application in cancer patients

Mitoxantrone is an anthracene derivative that acts as a cytostatic in a variety of cancers. A quantitative analytical method has been established for the determination of mitoxantrone in plasma. The method employed C 18 reversed-phase ion-pair chromatography with an isocratic mobile phase of 50.0% methanol in 10 m M phosphate buffer (pH 3.0) plus 0.09% 1-pentanesulphonic acid and ultraviolet detection. Sample preparation consisted of two extraction steps using same organic solvent system at different pH to remove plasma impurities efficiently. Potential adsorption of mitoxantrone onto glassware was considered. Silanization of all glassware with 5% dichlorodimethylsilane in chloroform increased the extraction recovery in plasma from 50 to 85% with high reproducibility. Mitoxantrone was unstable in human plasma. To maintain plasma sample integrity, each millilitre of sample should be fortified with 0.1 ml of 5% vitamin C (in citrate buffer) and kept frozen until analysis. Using this new method, the calibration curve of mitoxantrone in plasma in the range of interest (1–500 ng/ml) showed good linearity ( r = 0.996) and precision (both between-day and within-day coefficients of variation less than 10%). The lower detection limit of this assay method was 1 ng. The application of this method allowed us to study the stability of mitoxantrone in plasma, and the pharmacokinetics of mitoxantrone in nasopharyngeal carcinoma patients receiving 12 mg/m 2. The study revealed a prolonged terminal phase half-life for mitoxantrone.

Pharmacokinetics of mitoxantrone in man and laboratory animals.

Mitoxantrone (NOVANTRONE), an anthracenedione, is a novel anticancer agent with a wide spectrum of antitumor activity. Its anticancer activity is comparable to that of doxorubicin but with apparently significantly reduced cardiotoxicity. The recommended dosage regimen for the treatment of breast carcinoma is 12-14 mg/m2 given intravenously once every 21 days. Intravenously administered mitoxantrone disappears from the plasma of man and laboratory animals with multiexponential kinetics and with the terminal half-life ranging from 38 h to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues of the rat, dog, monkey, and man. However, redistribution back into the plasma and elimination from the body are slow processes. In both animals and man it is metabolized to the mono- and dicarboxylic acid derivatives, as well as glucuronide conjugates of these acids. Following intravenous administration, it is unchanged mitoxantrone that binds to most tissues. Rats, dogs, monkeys, and man, all eliminate mitoxantrone and its metabolites slowly by both renal and biliary excretion, with the biliary route predominating.