Showing papers by "Eva S. Schernhammer published in 1995"

Dexverapamil to overcome epirubicin resistance in advanced breast cancer

Abstract: Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.

Pharmacokinetic drug interaction between epirubicin and interferon-alpha-2b in serum and red blood cells.

Abstract: The influence of interferon-alpha-2b (CAS 99210-65-8, IFN) on the pharmacokinetics of epirubicin (CAS 56420-45-2, EPR) was investigated in 10 patients (4 male, 6 female). EPR was injected as an i.v. bolus over 2 min in a dose of 60 mg/m2 IFN was pre-administered 3 times a week in a dose of 5 x 10(6) IU as a s.c. injection. The comparison of the pharmacokinetics after injection of EPR and EPR+IFN did not show remarkable differences. A statistical significant influence in regard to the terminal elimination half-life (gamma-HL) and the total clearance (CLtot) was found, indicating a reduction of gamma-HL from 18.18 +/- 16.7 for EPR to 8.47 +/- 8.67 h for EPR+IFN and a reduction of the total clearance from 72.33 +/- 55.4 ml/min for EPR to 48.41 +/- 12.7 ml/min for EPR+IFN. The area under the concentration-time curve (AUC, according to the 3-compartment model) increases under the influence of IFN from 2004 +/- 1105 ng/ml.h for EPR up to 2582 +/- 1024 ng/ml.h for EPR+IFN. However, this increase is statistically irrelevant due to the high deviation ranges. Besides, the influence of IFN on the interactions of EPR with red blood cells (RBCs) was investigated in 6 patients under the above conditions. The percental concentration of EPR in RBCs is reduced from 35.4% to 34.7% after administration of IFN. Two metabolites, 13-dihydroepirubicin (M I) and 7-deoxydoxorubicinone (M II), were detected both in serum and RBCs, whereas IFN showed no significant interference with the metabolism or with the binding of the metabolites to RBCs.

Pharmacokinetic interaction between 4'-epidoxorubicin and the multidrug resistance reverting agent quinine.

Abstract: The serum and red blood cell (RBCs) disposition of epirubicin (EPR) after intravenous bolus injection without and with coadministered quinine ( QUI) was investigated in patients undergoing a cyclic chemotherapy with EPR. QUI possesses a statistical significant influence on the EPR serum concentrations and, as a consequence, on the pharmacokinetic parameters for the initial distribution phase of EPR. Within the first 15 min after administration, EPR was distributed from the central compartment distinctly faster in compare to the control, when QUI was preadministered (t(1/2) = 6 min for the control group and t(1/2) = 3 min with QUI; -46%, p < 0.05). Yet, in the beta-phase when drug-elimination predominates, no statistical significant influence of QUI in regard to EPR serum and RBC concentrations could be observed. Half-life of elimination was 0.5 h for the control group and 8.6 h for the QUI group (-10%). The mean initial serum concentration (co) was reduced significantly by QUI from 7359 +/- 506 ng/ml to 4351 +/- 1682 ng/ml (-42%, p < 0.005). Furthermore, QUI caused a reduction of the serum bioavailability of EPR (expressed as AUC(o-24)-values) from 3404 +/- 1008 ng/ml x h to 2359 +/- 1073 ng/ml x h (-31%, p < 0.05). Vd and Vdbeta were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 1487 ml/min, but due to the large standard deviations the calculated difference for these parameters was not statistically significant. In the observed time interval of 24 h, the red blood cell coefficient of distribution k(rbc) of EPR was lower if QUI was coadministered (k(rbc) = 1.25 +/- 0.12 for the control group k(rbc) = 1.15 +/- 0.13 under QUI; p < 0.04). The results point out that QUI induces an accelerated distribution of EPR from the blood into the tissue and that QUI additionally may have influence on the red-blood cell partitioning of EPR.

[Drug interactions between interferon alpha 2b and 5-fluorouracil during continuous intravenous 5FU infusion].

Abstract: The concentration-time profile of 5-fluorouracil (5FU) in serum of patients during continuous infusion of 5FU for five days was investigated. The coadministration of each of 5 million units interferon-alpha-2b (IFN) on day 2 and 4 of the infusion causes an accumulation of 5FU in the serum at about 120% on day 3 in compare to the control (day 1 of infusion without IFN). On day 5 of the infusion the mean 5FU serum concentrations are about 170% higher than on day 1 with a level of probability ranging from p < 0.0003 to p < 0.043. Mean AUC-values increase from 5454 ng/ml.h (day 1) to 12069 ng/ml.h (day 3, p < 0.05) and subsequently to 14919 ng/ml.h on day 5 (p < 0.005). IFN causes an decrease of the total body clearance from 2949 ml/h (day 1) to 1959 ml/h on day 3 and to 1258 ml/h on day 5 (p < 0.008), respectively. There might exist a linear correlation between the order of magnitude of the 5FU serum concentrations and its pharmacokinetic parameters on day 1, 3 and 5 and the administration of IFN, because a close correlation ranging from R = 0.972 to R = 0.999 have been found in regression analysis.