Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

PURPOSE: 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS: The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS: Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS: Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine.

High-dose cytarabine (HDARA-C) is an effective but toxic treatment for acute myeloid leukemia (AML). In order to reduce the incidence of severe complications noted with HDARA-C-containing regimens, we used a combination of intravenous (IV) idarubicin (IDARUB) at optimal dosage and cytarabine (ARA-C) at intermediate dosage. Thirty-five patients aged 23 to 78 years (median, 56) with AML in first relapse received IDARUB, 8 mg/m2/d for five days, and ARA-C, 1 g/m2 every 12 hours for six doses. Of the 35 patients, 21 achieved a complete remission (CR), four had a partial remission (PR), four died in aplasia, and six were nonresponders. The only factor influencing the CR rate was the duration of the first CR (35% for patients relapsing before 16 months v 83% for patients relapsing after 16 months, P = .003). Mucositis was the most significant extrahematologic side effect. Diarrhea, skin toxicity, and hepatic disturbances were rare and mild. There was no cerebellar toxicity, even in 25 patients greater than 50 years of age. This regimen is effective and well tolerated even in elderly patients, and could be used either as induction or consolidation therapy for the treatment of AML.

Pharmacokinetics of idarubicin after oral administration in elderly leukemic patients.

We have studied the plasma pharmacokinetics of idarubicin (4-demethoxy daunorubicin) in 11 elderly patients suffering from acute myeloblastic leukemia receiving orally 30 mg/m2 per day for 3 consecutive days. Idarubicin culminated in plasma 4 hr after administration and followed three similar time courses after the three administrations. Idarubicinol (13-dihydro-4-demethoxy daunorubicin) was the only fluorescent metabolite in plasma and no aglycone could be detected; idarubicinol concentration was always higher than that of unchanged idarubicin. Due to its protracted half-life (64 hr in this study), this metabolite progressively accumulated and the ratio of the areas under the curve (0-24) idarubicinol/idarubicin increased from day to day. By comparison to results obtained after i.v. administration of the drug in another study, the bioavailability of idarubicin alone can be estimated to about 21%, whereas the bioavailability of the sum idarubicin + idarubicinol is about 41%.

A prospective randomized trial of idarubicin vs daunorubicin in combination chemotherapy for acute myelogenous leukemia of the age group 55 to 75.

A prospective randomized study was conducted comparing the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myeloid leukemia (AML) between 55 and 75 years. A total of 220 patients were randomized to receive as induction chemotherapy cytosine arabinoside (Ara-C: 100 mg/m2/day; continuous infusion for 7 days) combined with either daunorubicin (DNR: 50 mg/m2/day, i.v. bolus for 3 days) (n=108) or idarubicin (IDA: 8 mg/m2/day, i.v. bolus for 5 days) (n=112). The complete remission (CR) rate was similar (P=0.296) after IDA (76/112; 68%) and DNR (66/108; 61%) (P=0.3). For patients aged 55-65, the CR rate was significantly higher after IDA (39/47; 83%) than after DNR (29/50; 58%) (P=0.007). Persistent leukemia was more frequent after DNR (26/108) than after IDA (13/112; P=0.015). Hematological and extra-hematological toxicities were similar. The CR patients were given a consolidation course of chemotherapy with Ara-C: 50 mg/m2/12 h, subcutaneously for 5 days, combined with either DNR:30 mg m2/day, i.v. bolus for 3 days or IDA:8 mg/m2/day i.v. bolus for 3 days according to the initial randomization, and then received a continuous maintenance treatment for 2 years. The survival and disease-free survival (DFS) were similar in both groups; there was no difference in the risk of relapse. However, there was a trend for a longer event-free survival (EFS) in the IDA group than for the DNR patients (P=0.07). Our results seem to indicate that IDA is probably more efficient than DNR for AML patients between 55 and 75 years, and confirm the data published in other studies comparing prospectively IDA and DNR in adults.

Vinorelbine (Navelbine) in the treatment of breast cancer: the European experience.

Phase II studies of vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) have been conducted mainly at a dose of 30 mg/m2/wk, and this schedule has been used extensively in the treatment of advanced breast cancer. Vinorelbine used in a first-line setting as a single agent in 25 patients with previously untreated advanced metastatic breast cancer produced objective responses in 15 patients (60%) and complete responses (CR) in five (20%). A large multicenter study to assess the response rate by the main site of disease involvement included 145 assessable patients. The overall response rate was 41% (10 CRs and 50 partial responses: skin, 70%; lymph nodes, 67%; primary tumor, 56%; lungs, 33%; measurable bone, 27%; and liver, 23%). The median time to disease progression was 25 weeks and the median overall survival duration was 18 months. Neutropenia was the principal toxicity with grade 3/4 suppression noted; however, this was not accompanied by serious infection (incidence of grade 3/4 infection < 1%). Other grade 3/4 toxicity also was uncommon. Another phase II study included 50 patients assessable for toxicity and response. The overall response rate was 50% (2% CRs). In a salvage setting (second- and third-line treatment), 33 patients were treated with an overall response rate of 30% (two CRs). Rates of toxicity were no greater than in first-line patients. The most notable results for combination vinorelbine therapy were with a schedule of vinorelbine 25 mg/m2 on days 1 and 8 and doxorubicin 50 mg/m2 on day 1, with cycles repeated every 21 days. The overall response rate for the 89 evaluable patients was 74% (19 [21%] CRs; 47 [53%] partial responses). These data indicate that vinorelbine is a highly active agent with a favorable toxicity profile in the treatment of breast cancer.

Pharmacokinetics of idarubicin after daily intravenous administration in leukemic patients.

We have studied the plasma pharmacokinetics of idarubicin (4-demethoxy-daunorubicin) in eight leukemia patients receiving five daily i.v. injections (7-9 mg/m2 per day) of this new anthracycline. For unchanged idarubicin, similar pharmacokinetic parameters were exhibited after the 1st and the 5th injection. Idarubicinol (13-dihydroidarubicin) was identified as the only detectable metabolite of idarubicin in plasma. Due to a protracted half-life (40 h) this compound progressively accumulated in plasma without the occurrence of peaks after the injections. This administration schedule provides therefore an interesting method of dose fractionation of a new anthracycline.

Oral idarubicin and low dose cytarabine as the initial treatment of acute myeloid leukemia in elderly patients.

Idarubicin (IDR) is an anthracycline that can be administered orally. Low dose cytarabine (LDARAC) has been commonly used in the treatment of acute myeloid leukemia (AML) in elderly patients. A comination of oral IDR (20 mg/m(2) for 3 days) and LDARAC (10 mg/m(2) q12 hours for 10 days) was given in 32 patients aged 65 to 82 years (median 76) with de novo AML. Eight patients whose marrow remained blastic by day 20 received a second course (IDR for 2 days and LDARAC for 5 days). Complete remission (CR) was achieved in 13 cases (40.5%), (one course 12, two courses 1). There was 1 early death, 3 deaths in aplasia, 2 partial remissions and 13 failures. All but 5 patients were entirely managed in hospital. The median duration of neutropenia was 18 days and only 1 patient obtained CR without therapeutic aplasia. The extrahematologic toxicity was mild with 3 reversible cardiac events. These results are comparable to those obtained with conventional chemotherapy and this regimen could be proposed as induction treatment of AML in elderly patients.

Idarubicin and high dose cytarabine: a new salvage treatment for refractory or relapsing non-Hodgkin's lymphoma.

Twenty three patients with relapsing (n = 11) or refractory (n = 12) non-Hodgkin's lymphoma (NHL) to one or two prior anthracycline based combination chemotherapy regimens were treated as second or third line regimen with 3 induction cycles of Idarubicin (IDA) (7 mg/m2/d i.v. d1-d3) and high dose cytarabine (HD Ara-C) (1 g/m2/12 h i.v. d1-d3), each cycle was repeated every 3 weeks. Responding patients received a maintenance therapy with monthly cycles of IDA: 15 mg/m2 d1-d3, Etoposide 100 mg/m2 d1-d3, both by oral route. Twenty two patients are evaluable and we observed 13 CR and 1 PR with an overall response rate of 61% (14/23: 95% Cl = 38.5% 80.3%). The median time to progression was 32 months (6.5 - 63 + m.). The response rate to IDA-HD Ara C was not different for patients with (n = 14) or without (n = 9) objective response to the last prior therapy. The main toxicity was hematological: all patients experienced grade 4 neutropenia and 22 patients had grade 4 thrombopenia, but there were no toxic deaths. IDA and HD-Ara-C combination is highly effective in refractory or relapsed. NHL. As hematological toxicity was the limiting factor for further escalation of dose-intensity, further studies might include hematopoietic growth factors support in the therapeutic scheme.

Improved bioavailability of a new oral preparation of medroxyprogesterone acetate.

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a less than 10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate.

Between July 1988 and May 1990, we treated 45 women with newly diagnosed, unilateral, nonmetastatic, inflammatory breast cancer with an intensive neoadjuvant chemotherapy regimen (FEC-HD) repeated every 21 days, followed by surgery or radiation therapy. Evaluation of efficacy performed 3 to 4 weeks after at least 2 cycles showed disappearance of inflammatory signs in 91% of the patients and improvement in the remaining 9%. With regard to primary tumor and lymph nodes, there were 13 (28.9%) clinical complete responses, 30 (66.6%) partial responses, and 2 (4.5%) without change. No progressive disease was observed. Hematologic toxicity from this regimen was high with grade 4 neutropenia observed at day 14 in 100% of the patients. Retreatment at day 21 was possible in 83% of the cycles. Grade 1 or 2 infections occurred in 102 cycles out of 176 (57.9%). Grade 3 infections were seen in 9 cycles (5%). No septicemia or septic shock occurred. No toxic death occurred. After induction chemotherapy, locoregional treatment consisted of modified radical mastectomy in 39 patients and radiotherapy alone in 6. The mastectomy specimen showed no residual invasive tumor (primary tumor and lymph nodes) in 10 cases (25.6%). Two patients judged as partial responders were in fact histologic complete responders. The clinical and histological response rates observed appeared very promising. For this reason we are currently testing FEC-HD with or without GCSF in a randomized multicenter trial with correction of neutropenia, disease-free survival, and overall survival as main end points.

Phase II study of oral idarubicin in elderly patients with advanced breast cancer.

Thirty-one elderly patients with measurable advanced breast cancer entered this phase II study. A dose of 15 mg/m2/day of Idarubicin (IDA) for 3 consecutive days every 3 weeks was given orally. Mean total cumulative dose of IDA received was 175 mg/m2 (range: 45-475 mg/m2). Mean number of cycles given was four (range: 1-15). Out of 27 evaluable patients, three achieved a complete response (CR), four had a partial response (PR) (CR + PR = 26 +/- 17%), nine showed no change, and 11 had a progressive disease. Median time to progression was 83 days (range: 19-728 days). Out of 26 patients evaluable for toxicity, hematologic toxicity at day 21 was moderate: neutropenia grades 3 and 4 = 16% of cycles: two patients had grade 1 thrombopenia; and three patients, grade 3. No cumulative hematologic toxicity was detected. Nonhematologic toxicities consisted of nausea and vomiting in 72% of patients [World Health Organization (WHO) grades 3 and 4 = 8%)] and alopecia in 76% (WHO grades 2-3 = 38%). Grade 1 stomatitis occurred in 4% of cycles. Chemotherapy was discontinued in one patient because of drop of left ventricular ejection fraction (LVEF) from 0.62 to 0.44 at a cumulative IDA dosage of 322 mg/m2. The results of this study show that IDA is an active drug in elderly patients with advanced breast cancer. Due to its simplicity of administration IDA deserves further investigations in combination with other drugs.

Clinical studies with new anthracyclines: epirubicin, idarubicin, esorubicin.

Analogue development is one of the most intensively pursued anticancer drugs research projects. The rationale in anthracycline analogue development followed by Farmitalia Carlo Erba has been the selection of agents with improved therapeutic index with respect to the parent structures, different spectrum of activity, reduced toxicity to the myocardium and oral route of administration. The clinical development is based on Phase I, II and III studies. However, the best definition in terms of activity and toxicity of an anticancer agent is accomplished with Phase II clinical trials, especially if they are comparative in a randomized fashion with the parent compound. Esorubicin has just started Phase II clinical testing. Phase I studies have shown hints of activity in several malignant diseases. Idarubicin has already been shown to be an important antileukaemic agent in Phase II-III studies. Moreover this compound is the first oral anthracycline that has shown activity in breast cancer, lymphomas and leukaemias, together with potential for reduced cardiac toxicity. Epirubicin, which is now in Phase III clinical development, has been shown to possess a better therapeutic index than doxorubicin since it induces less acute toxicities (nausea and vomiting, mucositis, myelosuppression) and less cardiotoxicity than its parent compound, without loss of activity in responsive tumours.

[News from the French cancer registry of Doubs (author's transl)]. / Registre des tumeurs du Doubs: application pratique.

Cancer Registry of Doubs (471 845 h, 5 260 km2), an area located in east part of France close the Swiss frontier, gave cancer rates in 1977 and 1978, for male and female, for urban and rural areas, with interesting comparisons with death in the period. Histological information was available in a percentage of 0.88, cases variable with different locations. It is possible to analyse the different histological sub types and grading among some cancer sites (gastric, large bowel, bronchus). Different modalities of treatment (surgery, radiotherapy, hormono and immunotherapy) applied to the 2 783 cases of cancer are analysed.

[French FAC vs FEC study in advanced breast cancer]. / Die französische FAC-vs-FEC-Studie bei fortgeschrittenen Mammakarzinomen.

239 patients were evaluable: 116 in the FAC arm, 123 in the FEC arm. There is no significant difference in the therapeutic responses between 2 regimens: 52 +/- 9% vs 49 +/- 9%. Duration of responses (273 vs 303 d) and overall survival were also similar. FEC appears less myelotoxic, less toxic also in terms nausea, vomiting and grade 3 alopecia than the adriamycin combination. 9 patients required treatment cessation due to grade 2 cardiac dysfunction with 3 CHF, against no case in the epirubicin regimen.