Time- and dose-related modifications in cardiac function in rats after single intravenous doses of epirubicin

Time-related changes in cardiac output have been studied in rats after the intravenous administration of a range of single doses of epirubicin. There was an initial decline in cardiac function in the first 4-12 weeks after drug treatment at a rate that appeared to be dose-related. After 12 weeks, an average cardiac output of approximately 70%, relative to control values, was maintained in animals that survived until the end of the study. This effect was independent of the drug dose, reflecting the death of animals in the higher dose groups. The incidence of drug-induced cardiotoxic deaths, the majority of which (approximately 62%) occurred within the first 12 weeks, was dose-related, and suggested a LD50 for cardiac-related mortality of 5.48 +/- 0.39 mg/kg. There appeared to be a relationship between the reduction in cardiac output at 12 weeks and the probability of a further deterioration in function. Animals showing a greater than 40% reduction in cardiac output at 12 weeks accounted for greater than 90% of all the additional deaths between 12 and 20 weeks. Rats showing a less than 40% reduction in cardiac output at 12 weeks had a very high probability of surviving without clinical signs, although with a persistently depressed cardiac function. These findings are similar to the trends demonstrated in the sparse clinical data and this supports the view that the present simple animal model is suitable for the investigation of cardiotoxicity after the administration of cardiotoxic cytotoxic drugs.     

Local and systemic effects of repeated intraperitoneal epirubicin treatment

The local toxicity, general morbidity and mortality of repeated intraperitoneal administration of epirubicin (0.5 mg/kg in 100 ml isotonic saline) was investigated using a rat model. This dose is equivalent to that which would be used in the human. After six perfusions, the incidence of peritoneal inflammation was similar in the epirubicin group and saline controls. The vesicant properties of the drug were reflected in a significantly higher incidence of peritoneal fibrosis (P = 0.0015) but adhesions were more common in the controls (29%) than in the epirubicin perfused animals (4%). Animals from both groups showed inflammatory collections within the liver. There were no chronic hepatic lesions such as fibrosis/cirrhosis. This may be owing to portal bacteraemia caused by repeated cannulation of the peritoneal cavity. Evidence of microabscess formation in the hepatic parenchyma was observed in both animals. No histologically demonstrable toxicity was observed in the heart or gastrointestinal tract of the animals included in this study. The mortality of the epirubicin treated rats (2/146 perfusions) was similar to that of the saline controls (2/84 perfusions). These findings indicate that repeated intraperitoneal perfusion with epirubicin is not associated with significant toxicity. This anthracycline is therefore suitable for prolonged cyclical intraperitoneal chemotherapy.     

Clinical toxicity of 4'-epi-doxorubicin (epirubicin)

Epirubicin is a new derivative of doxorubicin characterized by an improved spectrum of activity and a better therapeutic index. At equimolar doses and in comparative studies, epirubicin proved to induce less acute toxicity than doxorubicin, in particular less vomiting, hair loss and myelotoxicity. While giving a comparable response rate in randomized breast cancer studies, epirubicin also proved to be less cardiotoxic than doxorubicin. The reduced potential for cardiac toxicity of epirubicin versus doxorubicin has been shown both by functional assessment (radionuclide cinecardioangiography) and by histopathologic evaluation (endomyocardial biopsies) at equally myelosuppressive doses or at equal doses (equimolar). The lessened cardiotoxicity of epirubicin versus doxorubicin can be explained by the different pharmacokinetic and metabolic properties of these two agents: epirubicin has been found to have a more rapid pharmacokinetic plasma clearance and an additional metabolic pathway (unique glucuronidation).     

Pharmacokinetics and toxicity of two schedules of high dose epirubicin

Epirubicin, a stereoisomer of doxorubicin, is reported to have equal antitumor activity with lower cardiac and systemic toxicity. Recently the maximum tolerated dose of this drug has been revised upwards with reported increased response rates. However, the pharmacokinetics of epirubicin at high doses have never been reported. Accordingly, this study was designed to evaluate the pharmacokinetics of epirubicin when administered as either a 15-min i.v. bolus or a 6-h i.v. infusion in a phase I study at high doses. Nineteen patients with a variety of malignancies were given a total of 52 cycles of epirubicin at doses of 90 to 150 mg/m2 given once every 3 weeks. The maximum tolerated dose was 150 mg/m2 epirubicin given either as a bolus or as an infusion. The major dose-limiting toxicity was neutropenia. Interpatient variation occurred in the pharmacokinetics at each dose level but overall there were dose-dependent pharmacokinetics. This was manifested as a disproportionate increase in plasma levels and areas under the curve as the epirubicin dose was increased from 90 to 150 mg/m2. The pharmacokinetics of epirubicin could best be described by an open two-compartment model. Peak plasma concentrations were attained at a median of 12 min following the bolus injection and concentrations approached the steady state within a median of 55 min following the start of the 6-h infusion. Administration of the 150 mg/m2 dose over the 6 h compared to the bolus administration was associated with a 92% decrease in peak concentration from 3088 +/- 1503 to 234 +/- 126 ng/ml. This was not associated with an appreciable change in hematological or nonhematological toxicities. The median distribution half-life was 10 min and the median elimination half-life was 42.0 h. The cumulative renal excretion of the parent compound accounted for less than 2% of the administered dose. The major metabolites in both plasma and urine samples were 4'-O-beta-D-glucuronyl-4'-epidoxorubicin, 13-S-dihydro-4'-epidoxorubicin, and 4'-O-beta-D-glucuronyl-13-S-dihydro-4'-epidoxorubicin. This study demonstrates that a 135 mg/m2 bolus infusion given on a 3-weekly schedule is an appropriate initial dose for further clinical studies.     

Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity.

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m(2) by intravenous bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL. h v 1,717 ng/mL. h; P =.002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P =.012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.     

Increasing single epirubicin doses in advanced soft tissue sarcomas.

PURPOSE: To evaluate the maximum-tolerated dose and the clinical efficacy of epirubicin in patients with advanced soft tissue sarcoma. PATIENTS AND METHODS: Sixty-one patients were treated at three different epirubicin dose levels: 140 mg/m(2) (six patients), 160 mg/m(2) (52 patients), and 180 mg/m(2) (three patients). Cycles were repeated every 3 weeks for a maximum of eight cycles. The first two dose levels proved to be feasible and safe without dose-limiting toxicity (DLT). Because the first three patients entering the third dose level experienced DLT, subsequent patients received the next lower dose level. RESULTS: The overall response rate was 44% (95% confidence interval, +/- 12%), with six complete (10%) and 21 partial (34%) responses. Responses seemed related to epirubicin dose level, because the response rate was 17%, 44%, and 100% for the three dose levels (chi(2) test for trend, P =.02). Median response duration, median time to progression, and median overall survival were 10, 8, and 15 months, respectively. Myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; 31% of patients were febrile. Nonhematologic toxicity was mainly grades 1 and 2. The mean epirubicin dose-intensity was 49 mg/m(2) per week. CONCLUSION: The third epirubicin dose level (180 mg/m(2)) was the maximum-tolerated dose. The recommended drug dose for clinical use is 160 mg/m(2) every 3 weeks with hematopoietic support. Single high-dose epirubicin is effective as first-line treatment and should be preferentially used whenever a high response rate is important to allow the resection of an otherwise unresectable disease or whenever it might result in a significant symptomatic benefit.     

5—氟尿嘧啶腹腔和静脉化疗药代动力学的比较研究

Pharmacokinetic comparison of 5-Fluorouracil (5-Fu) administered ip versus iv was made in rabbits. Ip administration of bolus and large volume of 5-Fu could maintain high, stable and sustained concentration in the peritoneal cavity, portal vain and liver while sparing the systemic circulation. After iv bolus administration of 5-Fu, drug concentration in the systemic circulation was very high. Although iv administration of 5-Fu could lead to high concentration in the portal vein and liver, sustainment of concentration was relatively of short duration and the 5-Fu concentration was very low in the peritoneal fluid. The authors believe that ip chemotherapy has a significant pharmacokinetic advantage over the conventional iv route in preventing and treating recurrences in the peritoneal cavity and liver metastasis after surgery for gastro-intestinal malignancies.     

晚期胃癌静脉合并腹腔化疗近期疗效观察

目的：观察并评价静脉合并腹腔化疗治疗晚期胃癌的近期疗效及毒副反应。方法：用ELF方案（CF、5－Fu、VP16）静脉滴注加DDP腹腔化疗61例晚期胃癌病人，观察并记录近期疗效和毒副反应。结果：全组患者总有效率为57.4%，其中CR率为9.8%，毒副反应较轻，主要为白细胞下降发生率为95.1%，血小板下降发生率为27.8%。结论：静脉加腹腔化疗治疗晚期胃癌疗效肯定，毒副反应轻，值得临床研究应用。     

Pharmacokinetics and toxicity of intraperitoneal cisplatin combined with regional hyperthermia

Hyperthermia (HT) potentiates in vitro cytotoxicity of cisplatin, providing a rationale for HT enhancement of cisplatin effect in vivo. In this study, regional abdominal HT was combined with intraperitoneal (IP) cisplatin in canines to characterize temperature distributions, as well as pharmacokinetics and toxicity of IP cisplatin with and without HT. Cisplatin (65 mg/m2) in normal saline was administered IP with a two-hour dwell time in ten Beagle dogs. Five of the ten dogs were randomly selected to receive concurrent regional microwave-producing HT at approximately 41.5 degrees C (IP) for a 60-minute period. Systemic temperatures in heated animals ranged from 37 degrees C to 40 degrees C; IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP cisplatin concentrations were ten to 22 times greater than serum levels; the IP drug half-lives were 133 +/- 9 minutes and 68 +/- 15 minutes in heated and unheated dogs, respectively (P less than .001). Total concentrations of serum and urine cisplatin did not differ between the heated and unheated controls. The area under the concentration v time curve for free, ultrafilterable cisplatin in serum in units of percent minutes was 40 +/- 8 in heated and 60 +/- 7 in unheated controls (P = .006). Except for transient nausea and vomiting, no evidence of serious toxicity was observed in serum chemistries or histopathologic sections at 21 days post-treatment. Experiments involving in vitro incubation of cisplatin in normal saline were performed as a function of saline temperature; these showed that the amount of reactive cisplatin metabolites formed increased linearly with temperature by approximately 30% from 38 degrees C to 44 degrees C. This study supports the hypothesis that, with IP temperature elevation, there is an increased rate of generation and retention of reactive metabolites of cisplatin in the peritoneal cavity relative to unheated controls. In spite of these differences in pharmacokinetics, no significant toxicity was encountered. This study provides a model for treatment of IP malignancy such as ovarian carcinoma with IP cisplatin and regional HT.     

Advanced breast-cancer - a randomized study of different doses of epirubicin associated with fixed doses of cyclophosphamide and 5-Fluorouracil

A moderate increase in the dose of anthracycline could be feasible and of clinical benefit in advanced breast cancer. Between April 1991 and April 1994, 69 consecutive patients with recurrent or metastatic breast cancer were randomly treated with two regimens, including different dosages of epirubicin (75 versus 100 mg/m(2)) associated with the same dosage (600 mg/m(2)) of cyclophosphamide and 5-fluoruracil (75-FEC vs 100-FEC). Patients were planned to receive 6 courses at 21 day-intervals. Thirty-six patients received the 75-FEC regimen and 33 received the 100-FEC regimen. The two groups were comparable for age, menopausal status, disease-free interval, previous therapy, performance status and sites of disease: Over the whole study, the 100-FEC regimen has allowed a 18% actual increase in the epirubicin dosage over the 75-FEC regimen. Overall response rate was 56% for the 100-FEC and 51% for the 75-FEC, with the 100-FEC inducing some more complete responses than the 75-FEC (38% vs 23%). Survival (but not time to progression) tended to be longer with the 100- than with the 75-FEC (median: 20 vs 13 mos, p<0.09). Nonhematologic side effects Were similar. Hematologic toxicity was slightly higher with 100- than with 75-FEC, with granulocyte colony stimulating factors used to recycle in the scheduled time in the 15 and 4% of courses, respectively.     

A functional assessment of the relative cardiotoxicity of adriamycin and epirubicin in the rat

The cardiotoxicity of the two anthracyclines, adriamycin and epirubicin, were studied in 14-week-old Sprague-Dawley rats after the intravenous administration of single doses of 1-4 mg/kg of adriamycin and 2-6 mg/kg of epirubicin. These doses of the two drugs were well tolerated with little acute toxicity. Acute toxicity was characterised by a transient reduction in body weight with recovery within 14 days. The cardiac output of the rats was measured at 4-weekly intervals, for up to 20 weeks, using an external counting technique with the radioactive tracer, 99mTc. The time-related changes in cardiac function in the rat after adriamycin and epirubicin were similar. The time course of the changes in cardiac output were biphasic. There was an initial phase of rapid decline in cardiac output in the first 12 weeks (phase I) and a second phase of persistent depression in cardiac function (phase II) after 12 weeks. The late progression of anthracycline-induced cardiotoxicity could be predicted from the measurements of cardiac output at 12 weeks. The relative cardiotoxicity of adriamycin and epirubicin was evaluated from the reductions in cardiac output and from the incidence of deaths related to cardiotoxicity. Both methods of evaluation showed that adriamycin was approximately twice as cardiotoxic as epirubicin. This relationship was independent both of the dose level of drugs used and of the damage level used for the evaluation. Dose-response curves were steeper for adriamycin than for epirubicin. The present findings agree with the somewhat limited clinical data suggesting that the present rat model is highly predictive and clinically relevant.     

Chemotherapy in ovarian carcinoma: intravenous or intraperitoneal?

Although the majority of women with advanced ovarian carcinoma respond to cisplatin-based intravenous chemotherapy, long-term survival is experienced by less than 30 per cent of treated patients. Efforts to improve the efficacy of treatment have focused on dose intensification and direct drug delivery into the peritoneal cavity.     

What is the effect of adjusting epirubicin doses for body surface area?

Doses of cytotoxic drugs are routinely adjusted according to body surface area. We have evaluated this practice in 32 women with advanced breast cancer treated with single-agent epirubicin 12.5-120 mg m(-2). Epirubicin and its metabolites were measured by high-performance liquid chromatography (HPLC). Unadjusted plasma clearance was calculated from dose in mg, and adjusted clearance from dose in mg m(-2). Unadjusted clearance did not correlate with surface area, height, weight, per cent ideal body weight or body mass index. There was no difference in the coefficient of variation (CV) of adjusted and unadjusted clearance (39.4% and 37.7% respectively). The AUC that would have resulted from giving an unadjusted dose was calculated. This predicted AUC was accurate, unbiased and had the same CV as the actual AUC. Similarly, in 11 patients an analysis of actual and predicted neutropenia confirmed that unadjusted dosing would have had no significant effect on the pattern of myelosuppression. Normalization of epirubicin dosage according to surface area appears not to reduce either pharmacokinetic or pharmacodynamic variability.     

Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse

Summary The pharmacokinetics of doxorubicin in nude mice have been investigated following intravenous and intraperitoneal administration of single doses of 12 mg/kg. The areas under the concentration curves of doxorubicin in kidney, heart, and striated muscle following intraperitoneal administration were approximately half the areas following intravenous injection, whereas plasma and liver showed nearly identical concentrations after a distribution phase of 2 h. Only minor differences in pharmacokinetics were found between nude and normal mice.     

Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide.

PURPOSE: We reviewed follow-up of patients treated in 19 randomized trials of adjuvant epirubicin in early breast cancer to determine incidence, risk, and risk factors for subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: The patients (N = 9,796) were observed from the start of adjuvant treatment (53,080 patient-years). Cases of AML or MDS (AML/MDS) were reported, with disease characteristics. Incidence and cumulative risk were compared for possible risk factors, for assigned regimens, and for administered cumulative doses of epirubicin and cyclophosphamide. RESULTS: In 7,110 patients treated with epirubicin-containing regimens (92% of whom also received cyclophosphamide), 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose-intensity, and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (相似文献   

An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity

Purpose

Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity.

Methods

Data from a clinical study (n?=?24) of patients with breast cancer receiving adjuvant intravenous FE₁₀₀C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC).

Results

Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3?kg. LBM was associated with neutrophil nadir (r?=?0.5, P?=?0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2?kg, P?=?0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC.

Conclusion

To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs.     

Effect of repeated intraperitoneal chemotherapy with epirubicin on the hepatic transport of bile acids and their enterohepatic circulation

The effect of repeated intraperitoneal perfusion with epirubicin on the clearance of 14C-taurocholate by the liver and the enterohepatic circulation of the synthetic bile acid 75-SeHCAT were investigated using a rat model. After six treatments there was no significant difference in the transport rate constants (plasma to liver, liver to bile and liver to plasma) between and within the saline and epirubicin groups. Similarly, there were no differences detected between the groups for the parameters derived from these transport rate constants. Thus the initial plasma clearance after six perfusions was 39 +/- 9, and 36 +/- 11 ml/min/kg in the epirubicin and saline groups respectively. The excretory efficiency of the liver at this stage was identical: 67 +/- 10% in the epirubicin treated animals and 67 +/- 6% in the saline controls. A deterioration in the SeHCAT retention was observed after repeated intraperitoneal perfusion in both groups. This was significant only in the cytotoxic group, between the first and sixth epirubicin perfusion: 59 +/- 9% vs 48 +/- 9% at 24 h (P = 0.03), 31 +/- 8% vs 22 +/- 5% at 48 h (P = 0.019) and was not cumulative beyond this stage. These findings indicate that repeated intraperitoneal perfusion chemotherapy with epirubicin does not impair bile acid clearance by the hepatocyte. The decrease in the retention of SeHCAT is unlikely to be the result of epirubicin-induced ileal mucosal damage since the reduction was not cumulative beyond 48 h of administration of the compound.