Pharmacokinetics Of Epirubicin Research Articles

Determination of the effect of berberine on epirubicin concentration in MCF-7 cells by LC-MS/MS: The mechanism of synergism explained by intracellular pharmacokinetics

This study investigated the inhibitory effect of epirubicin combined with berberine on MCF-7 cell proliferation and explored intracellular pharmacokinetics. A CCK-8 assay was used to detect the inhibitory effect of epirubicin alone and in combination with berberine on MCF-7 cell proliferation in vitro. A rapid and sensitive LC-MS/MS method was developed and validated to detect epirubicin in MCF-7 cells. After incubation with epirubicin and berberine at different time points, MCF-7 cells were lysed and precipitated by acetonitrile to extract the analyte. Chromatographic separation was performed on a C18 column. Daunorubicin was selected as the internal standard. The analytical method was applied to determine the epirubicin concentration in MCF-7 cells. Berberine was found to enhance the inhibitory effect of epirubicin (1 μg/mL and 2 μg/mL) on the proliferation of MCF-7 cells (P < 0.05). LC-MS/MS analysis revealed that berberine significantly increased epirubicin concentration in MCF-7 cells at 8, 12, and 24 h (P < 0.05). The results suggest that berberine may enhance the inhibitory effect of epirubicin on cell proliferation by increasing the concentration of epirubicin in MCF-7 cells. The assay provides a basis for research on the intracellular pharmacokinetics of epirubicin and develops analytical methods for other cell-targeted drugs.

Development and Validation of Reversed-Phase HPLC Method for the Determination of Epirubicin and Its Application to the Pharmacokinetic Study of Epirubicin Loaded Polymeric Nanoparticle Formulations in Rats.

Epirubicin, commonly used as anticancer drug for various types of tumors like breast, liver, lung, stomach, ovaries, and bladder for its improved antitumor efficacy and safety. A rapid, sensitive, and reliable bioanalytical method was developed and validated for epirubicin using conventional reverse phase HPLC with UV detection. The developed method was successfully applied to investigate the pharmacokinetics of epirubicin after intravenous administration of a reference epirubicin and its designed nano-formulations to rats. C18 column was used in an isocratic mode for analyte elution at a flow rate of 1.0 mL/min with UV detection of 234 nm. The mobile phase was composed of acetonitrile 22% (channel A) and 0.025% tri fluoro-acetic acid in water (channel B). Ondansetron was added as an internal standard, and the plasma samples were analyzed after protein precipitation. A concentration range of 0.016-1.024 μg/mL was selected for the construction of calibration curves, with LLOQ of 0.016 μg/mL. Results showed that the value of AUC, half-life, and mean residence time of designed nano-formulation were bounce to 10, 9, and 11 times higher, when compared to the reference epirubicin after intravenous dose of 10 mg/kg of epirubicin to rats, respectively. The designed epirubicin nano-formulations achieved clinically significant pharmacokinetic values in rats. Current method will help epirubicin future research using clinical samples and drug bioequivalence studies on various novel formulations for drug safety purposes.

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).

Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

Use of a Glass Membrane Pumping Emulsification Device Improves Systemic and Tumor Pharmacokinetics in Rabbit VX2 Liver Tumor in Transarterial Chemoembolization.

To evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits. Epirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n= 24) and a 3-way-stopcock group (n= 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100-300-μm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope. The area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 μg min/mL and 0.13 ± 0.06 μg/mL, respectively, in the device group and 0.71 ± 0.45 μg min/mL and 0.22 ± 0.17 μg/mL, respectively, in the 3-way-stopcock group (P= .013 and P= .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 μg/g tissue, respectively (P= .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P= .039). Conventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.

Pharmacokinetic scaling of epirubicin using allometric and species-invariant time methods

The pharmacokinetics of epirubicin, an anthracycline, were investigated after intravenous bolus administration (5 mg/kg) in mice, rats, rabbits and dogs. Based on animal data, we predicted the following human pharmacokinetic parameters using allometric scaling: 120 and 35.2 L/h for total body clearance (CLt) using simple and maximum life-span potential (MLP)-corrected allometry, respectively; 702 L for steady-state volume of distribution (Vdss). The scaled Vdss value was twofold lower than the corresponding values in humans. However, the scaled CLt values were consistent with those clinically observed in humans (35.6–133.4 L/h). We also predicted human parameters using species-invariant time transformations (equivalent time, kallynochrons, apolysichrons and dienetichrons). The mean Vdss (854 L) obtained using kallynochrons and that derived from simple allometry were comparable. The lowest CLt (121 L/h) derived using kallynochrons was comparable to that obtained using simple allometry. The results of this study also indicated that the predicted human CLt generated using MLP-corrected allometry can be used for the selection of a safe dose for studies in healthy adult human volunteers. These results suggest that such approaches may be useful in designing pharmacokinetic studies for novel anthracyclines.

Validation of high-performance liqid chromatography method to determine epirubicin and its pharmacokinetics after intravenous bolus administration in rats

We investigated the pharmacokinetics of epirubicin, an anthracycline derivative antibiotics, after intravenous (i.v.) bolus administration in rats. To analyze epirubicin levels in the plasma, bile, urine and tissue samples, we developed an high-performance liqid chromatography (HPLC)-based method which was validated for a pharmacokinetic study by suitable criteria. The plasma concentration of epirubicin after i.v. bolus administration was rapidly disappeared within 10 min from the blood circulation. The mean plasma half-lives at α phase (t1/2α) when administered at the dose of 2, 5, 10, 25 and 50 mg/kg were 2.14–2.61 min. The values of t1/2β at the corresponding doses increased two folds (from 150 to 291 min) with increasing doses. The CLt values significantly decreased with the increase in dose. In contrast, Vdss values increased about 1.5 times with the increase in dose from 2 to 50 mg/kg. Of the various tissues, epirubicin mainly distributed to the kidney, lung, heart and liver after i.v. bolus administration. The epirubicin concentrations in various tissues at 24 h after i.v. bolus administration were below 1.0 μg/g tissue. Epirubicin was excreted largely in the bile after i.v. bolus administration at the dose of 2, 10 and 50 mg/kg. The cumulative amount of epirubicin in the urine 72 h after dosage represented 20 % of the amount excreted in the bile 12 h after high dosage, indicating that i.v. administered epirubicin was mainly excreted in the bile. In conclusion, epirubicin was rapidly cleared from the blood circulation and transferred to tissues such as the kidney and liver 2 h after i.v. bolus administration. Moreover, the majority of epirubicin appears to be excreted in the bile by 12 h after i.v. bolus administration.

Effect of low-protein diet on anthracycline pharmacokinetics and cardiotoxicity

Anthracyclines are broad spectrum anticancer drugs with dose-dependent cardiotoxicity. Protein malnutrition commonly occurs in cancer patients and is considered a risk factor for development of cardiotoxicity. This study was designed to assess the modulatory effect of protein malnutrition on the pharmacokinetics and drug disposition properties of a single dose of doxorubicin and epirubicin and how these possible changes will affect the degree of cardiotoxicity of these drugs. A single interperitoneal dose of 15 mg/kg of either doxorubicin or epirubicin was injected into rats fed with either normal protein diet or low-protein diet. The plasma concentration-time profiles of doxorubicin and epirubicin and their concentrations in different tissues were determined. Serum creatine kinase level was determined at different time intervals and histopathological examination of heart tissue was carried out. Protein malnutrition significantly altered the pharmacokinetics of doxorubicin and epirubicin, with a significant decrease in their elimination, and prolonged the exposure of the heart to these drugs. Histopathological examination and serum creatine kinase measurements supported the role of protein malnutrition in enhancement of anthracycline cardiotoxicity. If similar alteration in anthracyclines' pharmacokinetics occurs in malnourished cancer patients, protein malnutrition will be a risk factor for development of anthracycline cardiotoxicity and dose adjustment will be required in nutritionally deprived patients.

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

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. Data from a clinical study (n = 24) of patients with breast cancer receiving adjuvant intravenous FE(100)C 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). 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. 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.

Time-lapse Live Cell Imaging and Flow Analysis of Multidrug Resistance Reversal by Verapamil in Bladder Cancer Cell Lines

To examine the effects of verapamil on the intracellular drug pharmacokinetics of epirubicin using alternative dosing schedules. The results might inform the choices for optimizing clinical chemotherapy. Sensitive parental (MGH-U1) and multidrug resistant (MDR) (MGH-U1R and MGH-U1-MMC) bladder cancer cell lines were used. Fluorescence time-lapsed studies were performed on cells incubated with epirubicin alone or combined with verapamil. Flow cytometry was performed after the alternative dosing regimens. Verapamil reversed the epirubicin localization patterns in MDR cells. Time-lapse imaging showed that nuclear epirubicin accumulation in MDR cells with verapamil followed the parental curve. The maximal reversal took >60 minutes. Flow cytometry showed increased epirubicin uptake in MDR cells co-incubated with verapamil. Preincubation was not as effective as co-incubation. The results of our model indicate that longer exposure to MDR-class drugs, exemplified by epirubicin, increases uptake and the MDR reversing action of co-treatment with verapamil. The present results highlight the need for additional clinical trials of drug dosing and scheduling for combination intravesical chemotherapy regimens.

Phase I Dose Escalation Study With Irinotecan, Capecitabine, Epirubicin, and Granulocyte Colony-Stimulating Factor Support for Patients With Solid Malignancies

Preclinical studies using sequences of topoisomerase I and II inhibitors suggested synergism; preliminary clinical studies, resulting in enhanced antitumor responses, confirm this in selected malignancies. This study determined the maximum-tolerated dose (MTD), toxicity, and pharmacokinetics of irinotecan (CPT-11), capecitabine, and epirubicin in patients with metastatic adenocarcinoma of lung, breast, or gastrointestinal tract. Correlation of topoisomerase IIbeta was also done. Eligibility criteria included the following: documented adenocarcinoma of the lung, breast, or gastrointestinal tract, <3 prior chemotherapy regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, age > or =18 years, adequate organ function, and signed informed consent. Irinotecan was administered at 250 mg/m2 intravenously day 1 every 21-day cycle, but was reduced to 180 mg/m2 in cohort 2 due to toxicity. Capecitabine was administered at 750 mg/m2 twice daily days 2 to 14 in cohort 1 but only on days 2 to 7 from cohort 2 due to early neutropenia and to allow for prophylactic granulocyte colony-stimulating factor (GCSF) support. Epirubicin was administered at 40 mg/m2 in cohort 1, but reduced to 30 mg/m2 in cohort 2, then reescalated until the MTD was reached. Toxicity was assessed in 21 patients; response was assessed in 17 patients. The most common grade 3 to 4 toxicities included neutropenia (57.1%) and anemia (28.6%). The MTD of epirubicin was 50 mg/m2. In evaluable patients, there were 2 partial responses (11.8%) and 13 stable disease (76.5%); these correlated well with topoisomerase IIbeta. The recommended doses for phase II studies: irinotecan 180 mg/m2 day 1, epirubicin 50 mg/m2 day 2, and capecitabine 750 mg/m2 twice daily days 2 to 7 of each 21-day cycle. This combination is reasonably active and warrants evaluation in the phase II setting.

Effect of Acute Hepatic Failure on Epirubicin Pharmacokinetics after Intrahepatic Arterial Injection in Rats

In the case of cancer chemotherapy for hepatocellular carcinoma, anthracycline anticancer agents such as epirubicin are widely used, and have typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. The anthracyclines are eliminated primarily by the liver, and the use of these drugs in patients with hepatic failure can be difficult. In this study, we investigated the effect of acute hepatic failure on the pharmacokinetics of epirubicin after i.a. injection in rats. Experimental acute hepatic failure was induced by carbon tetrachloride-treatment. Epirubicin was injected into the hepatic artery or the saphenous vein of the rats at a dose of 2 mg/kg. After both intravenous (i.v.) and i.a. injection, the serum concentration and the AUC 0-24 of epirubicin in hepatic failure rats were significantly higher than the values in control rats. The AUC 0-24 ratio of hepatic failure (i.a.) to control (i.a.) was higher than the ratio of hepatic failure (i.v.) to control (i.v.). These results suggest that the influence of hepatic failure on serum epirubicin concentration is larger with the i.a. route than with the i.v. route. The liver concentration of epirubicin after i.a. administration in hepatic failure rats was significantly lower than that in control rats. This result suggests that the effect of the liver-selective drug targeting after i.a. injection in hepatic failure rats is lower than in normal rats. Therefore, we should be careful when administering epirubicin by the i.a. route in patients with acute hepatic failure.

Plasma and Tissue Pharmacokinetics of Epirubicin and Paclitaxel in Patients Receiving Neoadjuvant Chemotherapy for Locally Advanced Primary Breast Cancer

The objective of the study was to assess individual distribution of antineoplastic drugs into the tumor. Twelve advanced-stage primary breast cancer patients with neoadjuvant epirubicin+paclitaxel chemotherapy were studied. Plasma concentrations of epirubicin and paclitaxel were monitored for 24 h. Epirubicin concentrations in subcutaneous and tumor tissues were measured using microdialysis up to 12 h postdose. Epirubicin concentrations were described by a compartmental population pharmacokinetic model (NONMEM). Noncompartmental analysis was used for paclitaxel. Plasma pharmacokinetics corresponded to published data. Mean epirubicin exposure in the tumor and in subcutaneous tissue was very similar, but tissue Cmax and area under the curve values reached only (means) 1% and 11%, respectively, of plasma values. Epirubicin doses were significantly correlated to tumor exposure irrespective of body surface area. There is no specific barrier for epirubicin to reach primary breast cancer tumors.

A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer

Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines. We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m(2)) in combination with escalating oral doses of sulindac (0-800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3. Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease. Epirubicin 75 mg/m(2) and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.

Phase I trial of the histone deacetylase inhibitor, valproic acid and the topoisomerase II inhibitor, epirubicin: A clinical and translational Study

3084 Background: Pre-clinical data show that histone deacetylase inhibitors(HDACi) potentiate the DNA damage induced by topoisomerase II inhibitors (topo II). Exposure to HDACi results in histone hyperacetylation and chromatin decondensation thereby facilitating the access of topo II inhibitors to DNA. Valproic acid (VPA) is a well-tolerated, orally bio-available, anti-seizure drug that has recently been shown to inhibit HDAC. Epirubicin is a widely utilized topo II inhibitor with a favorable toxicity profile. Methods: A Phase I dose escalation study explored the toxicity, efficacy and the pharmacokinetics (PK) of VPA and epirubicin. Histone acetylation and topo II expression was evaluated in tumor samples and peripheral blood mononuclear cells (PBMC). VPA was administered as an IV loading dose followed by 5 doses of oral VPA given every 12 hours. Epirubicin was infused on day 3. Treatment cycles were repeated at 3 week intervals and tumor restaging was done every 2 cycles. Enrollment was opened to all metastatic solid tumors. Results: To date, 16 patients (pts) [8 females, median age 62 (44–78)] have been treated at 4 dose levels: VPA 15, 30, 45, and 60 mg/kg; with epirubicin at 75 mg/m2. The maximum tolerated dose has not been reached and dose escalation is continuing. Tumor types enrolled included: 8 melanoma (8), breast (5), cervical, lung, and adrenal carcinoma. The most common treatment related adverse events encountered included neutropenia (69%, G3/4), anemia (6% G1/3), nausea (31%, G1/2) and fatigue (25%, G1/2). Radiation recall was seen in all patients with prior radiation (6 pts). Major responses were observed in all tumor types including in anthracycline failures and in anthracycline-resistant cancers such as melanoma and cervical carcinoma (CR/PR 4/13; SD 3/13; PD 6/13). VPA PK data showed a linear increase with dose. Conclusions: A sequence-specific combination using the HDACi, VPA and epirubicin is feasible and with acceptable toxicity. VPA plasma levels exceeded concentrations needed for in-vitro synergy. The significant anti-tumor activity seen in this heavily pretreated patient population warrants further exploration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer

Reversion of Chemoresistance in Aggressive Lymphoma by Quinine. A Phase II Trial.

Multidrug resistance has been one of the most studied mechanisms of cancer cell resistance to chemotherapy. Evidence of its involvement in hematological malignancies is known since many years. One well-designed phase I trial showed that about 20 to 25% of patients strictly resistant to EPOCH schedule could become responsive again by the addition of Dex-verapamil (J Clin Oncol 1995; 13: 1995–2004). We decided to perform a phase II trial to evaluate whether quinine could reverse resistance to chemotherapy in aggressive lymphoma. Methods: Patients included had all received at least two lines of chemotherapy including CEOP (cyclophosphamide 750mg/m2, epirubicine 60mg/m2, vincristine 1.4mg/m2 IV day 1 and prednisone 40mg/m2 orally day1 to day 7) and were demonstrated as strictly refractory to CEOP i.e. either no change or progression. Q-CEOP was administered as follows: quinine 30-mg/kg/day for two days from d0 to d1 as a continuous infusion, CEOP at the beginning of d1. Results: 15 patients have been included with the following characteristics: median age: 52 years (32–64), 66% stage III–IV, 60% elevated LDH. The median number of previous regimens was 3 (2–5). 13 patients had diffuse large B cell lymphoma including 3 with previous history of follicular lymphoma. Two had mantle cell lymphoma. Seven patients were included directly since they were initially refractory to CEOP while eight were shown refractory after two further cycles of CEOP. Epirubicin pharmacokinetics was not influenced by quinine. Mean dose intensity of epirubicin was 94%. Toxicity was mild. 4 responses were observed at the end of treatment including 2 complete and 2 partial responses (26%, IC 95%: 8–55%). Only the 2 CR patients are still alive with no evidence of disease at 35+ and 61+ months. Conclusion: These results add further arguments to confirm that MDR1 plays a significant role in resistance to chemotherapy in lymphoma. Quinine allowed unexpected long term remission in 2 responding patients.

563 Pharmacokinetics of epirubicin and paclitaxel during weekly administration in patients with metastasised breast cancer

563 Pharmacokinetics of epirubicin and paclitaxel during weekly administration in patients with metastasised breast cancer

Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients

BackgroundAnthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites. Patients and methodsWomen with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m2 i.v. bolus followed by docetaxel 75 mg/m2 in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m2, then 2 mg/m2 weekly thereafter) in a 30-min infusion. Epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). ResultsNo pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration–time curve (AUC0–24 h) was 1230 ± 318 [mean ± standard deviation (SD)] at the first cycle and 1287 ± 385 h·µg/l at the sixth. The mean (±SD) maximum plasma concentration (Cmax) and the terminal elimination half-life at the first cycle (1303 ± 490 µg/l and 12.5±3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 ± 580 µg/l and 11.5±2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. ConclusionEnhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.

A population model of epirubicin pharmacokinetics and application to dosage guidelines.

To use a population approach to identify readily available clinical or biochemical characteristics that influence the pharmacokinetics of epirubicin and to develop new dosage guidelines based on these results. Data were available from 109 patients with advanced breast cancer, 72 of whom were known to have liver metastases. They were treated with single-agent epirubicin 12.5 to 120 mg/m(2). Analysis was performed using the software package NONMEM and a three-compartment model was fitted to the data. Individual clearance (CL) estimates ranged from 4 to 86 l/h and the final model included CL as a function of aspartate aminotransferase (AST): CL (l/h)=72.9-(72.9x0.135xlnAST). Inclusion of this factor reduced the interindividual variability in CL from 49% to 39%. Using a target AUC of 4000 ng.h/ml, the following doses were predicted to achieve this exposure with the greatest precision: AST <150 IU/l 125 mg; AST 150-250 IU/l 90 mg; AST 250-500 IU/l 60 mg; AST >500 IU/l 30 mg. These new guidelines were compared with three other guidelines based on serum bilirubin or AST concentrations and body surface area (BSA). The new guidelines achieved the target with greater precision (root mean squared error, rmse, 39.0%) than the current UK guidelines, current USA guidelines or an earlier equation based on AST (rmse 63%, 62% and 59%, respectively). The proposed dosing guidelines should reduce variability in systemic exposure to epirubicin more effectively than traditional approaches. In addition, as they do not require adjustment according to BSA, they could reduce dosage preparation time and the potential for prescribing and dispensing errors.

Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer

BackgroundThe objectives of this study were to investigate the disposition of gemcitabine, epirubicin, paclitaxel, 2′,2′-difluorodeoxyuridine and epirubicinol, and characterize the pharmacokinetic and pharmacodynamic profile of treatment in patients with breast cancer. Patients and methodsThe drug dispostion in 15 patients who received gemcitabine 1000 mg/m2, epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (EP, n = 6) and epirubicin90 mg/m2 alone (n = 6). Drug and metabolite levels in plasma and urine were assessed by high-performance liquid chromatography and parameters of drug exposure were related to hematological toxicity by a sigmoid-maximum effect (Emax) model. ResultsPaclitaxel administration significantly increased the epirubicinol area under the concentration–time curve, from 357 ± 146 (epirubicin) to 603 ± 107 (EP) and 640 ± 81 h × νg/ml (GEP), and reduced the renal clearance of epirubicin and epirubicinol by 38 and 52.2% and 34.5 and 53% in GEP- and EP-treated patients, respectively, compared with epirubicin alone. Gemcitabine had no apparent effect on paclitaxel and epirubicin pharmacokinetics, and renal clearance of epirubicin and epirubicinol. The only pharmacokinetic/pharmacodynamic relationship observed was between neutropenia and the time spent above the threshold plasma level of 0.1 µmol/l (tC0.1) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et50) of GEP being 7.8 h, similar to that of EP. ConclusionsPaclitaxel and/or its vehicle, Cremophor EL, interferes with the disposition and renal excretion of epirubicin and epirubicinol; gemcitabine has no affect on epirubicin and paclitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine.

Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats

There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg(-1) per week) or as a single dose injection (20 mg kg(-1)). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameterto correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin.