Stop-flow technique for loco-regional delivery of high dose chemotherapy in the treatment of advanced pelvic cancers.

AIM: To verify the rationale of a pelvic stop-flow technique for the perfusion of high-doses of mitomycin C and anthacyclines in patients with inoperable, recurrent pelvic cancer. METHODS: The stop-flow technique was realized by using percutaneous double-balloon arterial-venous catheters that selectively isolate the pelvic vascular section and a perfusion provided by an extracorporeal pump for 20 min. Ten patients (pts) with unresectable pelvic recurrence from colon-rectal cancer were treated with a combination of Mitomycin C (MMC, 20 mg/sqm) plus doxorubicin (DOXO, 75 mg/sqm; 8pts) or epirubicin (EPI, 75 mg/sqm; 2pts) infused into the isolated pelvic compartment. Blood samples were collected from the extracorporeal vascular flow and from peripheral plasma, and analysed for drug quantitation. RESULTS: During the procedure, there were no technical or hemodynamic complications, and no deaths occurred during surgery or in the postoperative period. MMC and DOXO peak levels measured in the extracorporeal system which irrotates the tumor area, were on average 21.6 (range: 4.3-44.3, MMC) and 17.2 (range: 1.8-48.4, DOXO) times higher than those observed in the peripheral blood. Similarly; the area under concentration (AUC) versus time curves measured in the pelvic compartment during stop-flow perfusion were 19.9 (range: 3.8-45.0, MMC) and 13.4 (range: 1.2-26.6, DOXO) times higher than the corresponding value in peripheral circulation. The drug percentage eliminated in the ultra filtrate was only 7.7% (MMC) and 0.9% (DOXO), and the plasmatic AUC(0-24) were similar to those observed with iv bolus of equivalent drug doses. Minimal systemic and local toxicities were observed. One complete pathological and 2 partial responses were observed; pain remission in 8/10 patients. median survival was 12 months (8-31). CONCLUSION: The endo-arterial administration into the local vasculature produces high pelvic-systemic concentration gradients during the stop-flow perfusion with limited local and systemic toxicity. The encouraging clinical results suggest further evaluation.

A double-blind evaluation of the analgesic efficacy and toxicity of oral ketorolac and diclofenac in cancer pain. The TD/10 recordati Protocol Study Group.

AIM: To compare the analgesic efficacy and toxicity of the nonsteroidal anti-inflammatory analgesic drug, ketorolac (Toradol, Recordati spa, Milan) 10 mg p.o. (t.i.d.) with diclofenac (Voltaren, Novartis Farma, Origglo, VA) 50 mg p.o. (t.i.d.) in cancer patients with moderate to severe chronic pain. METHODS AND STUDY DESIGN: The study was a multicenter randomized double-blind cross-over trial. Each treatment lasted 7 days, after which the patients crossed over to the other drug. Pain intensity was evaluated by the visual analogue scale (VAS) after the first dose and by the 5-point verbal rating scale (VRS) by the patient and by the physician following the 7-day treatment. RESULTS AND CONCLUSIONS: A total of 138 advanced cancer patients were enrolled in the study. Overall 251 single-dose administrations (117 cross-over observations) and 257 multiple treatments (127 cross-over experiments) were assessable. After a single administration of ketorolac and diclofenac, no significant difference could be observed in analgesic activity, as indicated by the area under the pain-intensity time curve (AUC0-8), in the maximum efficacy, or the duration of efficacy of the two drugs. The Westlake confidence intervals of the AUC0-8 ratio (ketorolac: diclofenac) (1.07; 90% CI, 0.94-1.19), of the maximum efficacy ratio (1.03; 90% CI, 0.92-1.14), and the duration of efficacy ratio (1.05; 90% CI, 0.97-1.11) showed the bioequivalence of the two drugs. Satisfactory pain relief was reported for multiple 7-day treatments, with no significant differences between the two therapies: according to the physician's evaluation, in 93/128 (73%; 95% CI, 65-80%) ketorolac treatments and 91/129 (71%; 95% CI, 63-78%) diclofenac treatments; according to the patient's evaluation, in 83/128 cases (65%; 95% CI, 57-73%) after ketorolac and in 74/129 cases (57%; 95% CI, 49-66%) after diclofenac. Adverse symptoms were acceptable with both drugs. Interestingly, a pronounced sequence effect was found: gastric disturbances after ketorolac were observed mainly (10 out of 15 observed events) when the drug was given to patients pretreated with diclofenac.

Comparative crossover trial of two intravenous doses of granisetron (1 mg vs 3 mg) + dexamethasone in the prevention of acute cis-platinum-induced emesis.

BACKGROUND: The 5HT3 receptor antagonist Granisetron (GRA) is available on the market as a 1 mg vial in USA and as a 3 mg vial in Europe. This study aimed to compare the two i.v. doses of GRA (3 mg vs 1 mg), both of which combined with Dexamethasone (DEX) (20 mg) in the prevention of acute Cisplatinum (CP)-induced emesis. PATIENTS AND METHODS: One hundred and ninety-eight consecutive chemotherapy-naive cancer patients, mainly suffering from lung and bladder cancer, were randomized at their first cycle to receive either GRA 1 mg + DEX or GRA 3 mg + DEX as i.v. bolus prior to chemotherapy and crossed-over to another GRA dose at the second cycle. The cytotoxic treatment included different multi-drug regimens containing CP (median dose 60 mg/m2, range 50-70) administered on day 1 and repeated every 21-28 days. RESULTS: Of the 192 evaluable patients complete protection from acute emesis with GRA 1 and GRA 3, was observed after the 1st + 2nd cycles as follows: nausea 70% and 74%, vomiting 90% and 94%, nausea and vomiting 67% and 74% respectively (no statistically significant difference). No carry-over effect was observed on the complete protection from emesis. The crossover analysis comprising 156 patients confirmed there were no differences between the two antiemetic treatments. Twenty-seven per cent of patients preferred GRA 1, 31% preferred GRA 3, while 42% expressed no preference (P = 0.75). Nor was any difference observed for tolerability, the only reported side-effects being mild headache (16% vs 17%) and constipation (18% vs 25%). CONCLUSION: This study shows that, under the above conditions, the 1 mg and 3 mg i.v. GRA doses are comparably effective when combined with DEX 20 mg in the prevention of acute CP-induced emesis.

Pharmacokinetic evaluation of two different formulations of megestrol acetate in patients with advanced malignancies.

The bioequivalence of two megestrol acetate formulations, 160-mg "tablets" and 160-mg "sachets," was investigated in a single-dose, open-label, balanced-for-sequence cross-over study involving 12 advanced-cancer patients. The observed plasma megestrol-acetate time course obtained with both formulations was consistent with the literature data. The main source of variability in the pharmacokinetic parameters was intersubject variability; drug formulation played only a minor (and nonsignificant) role. The width of the 90% confidence interval of the area-under-the-curve (AUC) ratio (sachets: tablets) computed according to Schuirmann (0.9-1.4) was mainly due to the presence of a single outlier, showing an AUC ratio of 2.7. The trend to higher bioavailability of the new formulation was not significant, especially as compared with the dose-response data reported in the literature.

Aminoglutethimide in advanced breast cancer: prospective, randomized comparison of two dose levels. Italian Cooperative Group.

In a multicenter randomized clinical trial 106 post-menopausal patients with progressive metastatic breast cancer were allocated to receive 500 mg or 1000 mg Aminoglutethimide (AG) per os daily. Cortisone Acetate (CA) replacement dose was 37.5 mg/day orally in both groups. In 91 fully evaluable patients, no statistically significant difference was observed between the two therapeutic regimens, neither in terms of overall response (28 vs 35%) and by site responses, nor in terms of median time to progression (10.5 vs 14.5 months) and median overall survival (20 vs. 22 months). The tolerability was satisfactory in both regimens. Although no statistically significant differences occurred, in the low dose regimen we observed fewer patients with side-effects (25% vs 6%) and induced grade 3 side-effects (4% vs 9%). Our results confirm that AG daily doses of 500 and 1000 mg associated with corticosteroids have a comparable effect. Because of its slight but clinically noticeable better tolerability, the lower dose is the preferable regimen in the treatment of advanced breast cancer.

Epirubicin metabolism and pharmacokinetics after conventional- and high-dose intravenous administration: a cross-over study.

In a pharmacokinetics study, six patients were treated i.v. with epirubicin (EPI) at the two dose levels of 60 and 120 mg/m2, whereas a further six patients were treated at 75 and 150 mg/m2. Both groups were studied according to a balanced cross-over design; the aim of the study was to assess the pharmacokinetic linearity of epirubicin given at high doses. Both the absolute goodness of fit and the Akaike Information Criterion (AIC) point to a linear, tricompartmental open model as the choice framework for discussing EPI plasma disposition after 16/24 administrations, independent of the delivered dose. After 8 treatments, the minimal AIC value corresponded to a nonlinear tissue-binding model. However, even in these cases, second-order effects were present only during the early minutes following treatment. In a model-independent framework, mean EPI plasma clearance was identical at the two dose levels of 60 and 120 mg/m2 (65.4 +/- 8.0 vs 65.3 +/- 13.4 l/h, P = 0.92). Both the mean residence time (MRT) and the volume of distribution at steady-state (VSS) were similar as well (MRT: 22.6 +/- 2.9 vs 24.2 +/- 3.7 h; P = 0.46; VSS: 21.3 +/- 1.5 vs 22.6 +/- 6.5 l/kg, P = 0.46). No statistically significant difference could be found in mean statistical-moment-theory parameters determined after 75- and 150-mg/m2 EPI doses (plasma clearance, PlCl: 83.4 +/- 13.5 vs 68.5 +/- 12.8 l/h, P = 0.12; MRT: 22.6 +/- 4.8 vs 21.9 +/- 3.9 h, P = 0.60; VSS: 26.7 +/- 10.5 vs 21.2 +/- 7.0 l/kg, P = 0.17). Analysis of variance also failed to reveal any significant correlation between dose and plasma clearance. However, when data relative to single patients were examined, a trend toward nonlinear drug distribution as well as a consequent increase in peripheral bioavailability could be observed in 4/6 patients of the 75-mg/m2 vs the 150-mg/m2 group.(ABSTRACT TRUNCATED AT 400 WORDS)

High-performance liquid chromatographic analysis of idarubicin and fluorescent metabolites in biological fluids.

A specific, sensitive, and reliable high-performance liquid chromatographic (HPLC) method for the determination of idarubicin (IDA) and its known fluorescent metabolites idarubicinol (IDAol) and 4-demethoxy-daunomycinone (AG1) in biological fluids (human plasma and urine) was developed and tested. Plasma samples were solid-phase-extracted (C18 bonded silica cartridges). Complete separation of unchanged drugs and metabolites was achieved on a Cyanopropyl chromatographic column (25 cm x 4.6 mm inside diameter; particle size, 5 microns) using fluorescence detection (excitation wavelength, 470 nm; emission wavelength, 580 nm). Sensitivity was better than 0.2 ng/ml for all analytes; rates of recovery of unchanged drug and metabolites were better than 84.5% (IDA), 80.3% (IDAol), and 83.9% (AG1). The interassay coefficient of variation was 6.5% for IDA, 5.8% for IDAol, and 9.8% for AG1. Mean intra-assay precision was 4.6% for IDA, 5.9% for IDAol, and 5.0% for AG1 at sample concentrations of above 1 ng/ml and 12.1% for IDA, 10.8% for IDAol, and 14.1% for AG1 at sample concentrations of below 1 ng/ml.

Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study.

The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoglutethimide in advanced breast cancer: plasma levels and clinical results after low and high doses.

Drug plasma levels, metabolism data and clinical results were evaluated after the daily administration of either 500 or 1,000 mg aminoglutethimide (AG, Orimeten, Ciba-Geigy) plus hydrocortisone acetate (20 mg b. i. d.). A total of 34 patients with advanced breast cancer entered the study: 17 were given 1,000 mg/day and 17 received 500 mg/day for at least 3 months. A novel HPLC method was developed to determine the levels of AG and its known metabolites [N-acetyl-AG (NAG), formyl-AG, nitroglutethimide, hydroxy-AG] in the biological samples. AG plasma concentration was significantly higher during the 1,000-mg/day regimen. NAG was the only metabolite observed in plasma, always occurring at concentrations lower than those of the parent drug. The ratios between NAG and AG levels distinguish two statistically different groups of patients. Irrespective of the dose, a partial response was observed in 44% of the patients; no change in 32% of cases; and progressive disease had an incidence of 24%. The probability of response was not dependent on the drug AUC or on the NAG/AG ratio and did not significantly depend on previous hormone treatment. Neither the plasmatic level of the AG or metabolite concentrations nor the NAG/AG ratio seemed to affect the incidence of side effects.

Adjuvant therapy for operable breast cancer with medroxyprogesterone acetate alone in postmenopausal patients or in combination with CMF in premenopausal patients.

The present paper concerns two multicenter studies on adjuvant therapy with medroxyprogesterone acetate (MAP) for operable N+ breast cancer. The patients entered the study between April 1979 and March 1986. One hundred and fifty-one premenopausal patients were randomly assigned to receive either polychemotherapy (CMF) or CMF + MAP. One hundred and thirty-eight postmenopausal patients were randomized to receive either MAP h.d. or no treatment. CMF was administered according the following schedule: cyclophosphamide mg 100/ms p.o. 1-4 days; methotrexate mg 40/ms i.v. and fluorouracil mg 600/ms i.v. 1st and 8th days. The cycle was repeated six times every 28 days. MAP was administered at 1000 mg X 2/daily p.o. for 30 days and afterwards 500 mg X 2/daily for 5 months. In the premenopausal study after a median follow-up of 36 months no difference was observed in the incidence of recurrence, site of recurrence, actuarial 5-year disease-free survival (DFS) or overall survival (OS). In the postmenopausal study a statistically significant lower number of recurrences was observed in MAP-treatment patients after a median follow-up of 37 months. The effect of MAP was limited to patients with less than or equal to 3 metastatic axillary lymph nodes. In addition, there are suggestions that only patients with ER+ tumors draw some advantage from the treatment. On the other hand, no difference exists in the OS. The treatments were substantially well tolerated. The MAP + CMF regimen induces lower vomiting compared to the CMF alone. The most frequent MAP side-effects were vaginal spotting (16%) and tremors (12%). We conclude that MAP h.d., like tamoxifen and aminoglutethimide, can improve the DFS of operable N+ breast cancer in postmenopausal patients.

HPLC analysis of doxorubicin, epirubicin and fluorescent metabolites in biological fluids.

A specific, sensitive and reliable HPLC method for the determination of doxorubicin (DX), epirubicin (epiDX) and their known fluorescent metabolites [doxorubicinol (DXol), epirubicinol (epiDXol) 7-deoxy-adriamycinone (metabolite C), adriamycinone (metabolite D), 7-deoxy-13-dihydro-adriamycinone (metabolite E), 13-dihydro-adriamycinone (metabolite F), 4'-O-beta-D-glucuronyl-4'-epiDX (metabolite G) and 4'-O-beta-D-glucuronly 13-dihydro-4'-epiDX (metabolite H)] in biological fluids (human plasma, bile and urine) has been developed and tested. Plasma samples were solid-phase-extracted (C18-bonded silica cartridges). Urine and bile samples were injected directly after the addition of the internal standard and dilution with 0.3 M phosphoric acid. Complete separation of unchanged drugs and metabolites was achieved with a mobile phase consisting of 75.6% 10 mM KH2PO4 and 24.4% CH3CN (the pH of the solution was adjusted to 4.3 with 0.03 M H3PO4) at a flow rate of 1.5 ml/min. For the analyses we used a cyanopropyl chromatographic column (25 cm x 4.6 mm i.d.; particle size 5 micron) and fluorescence detection with excitation wavelength set at 470 nm and emission at 580 nm. Sensitivity was better than 0.3 ng/ml for all substances analysed. The mean absolute recovery of unchanged drugs and metabolites was between 88.3% (metabolite E) and 98.92% (metabolite G). Intra- and interassay precisions (plasma samples) were better than 10.6% and 13.0%.

Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study.

The pharmacokinetics and metabolism of doxorubicin (DX) and epirubicin (epiDX) were investigated in eight cancer patients who received 60 mg/m2 of both drugs independently by intravenous (i.v.) bolus at 3-week intervals according to a balanced cross-over design. Unchanged DX and epiDX plasma levels followed a triexponential decay. Half-lives (t/2) of the three decay phases were longer for DX (t/2 alpha: 4.8 vs. 3 min; t/2 beta 2.57 h vs. 1.09 h; t/2 gamma 48.4 vs. 31.2 h). According to a model-independent analysis, the different plasma disposition kinetics of the two compounds appears to be related to a higher plasma clearance (PlCl) and to a lower mean residence time (MRT) of epiDX (PlCl: 75.0 l/h, range: 35.6-133.4 l/h; MRT: 31.6 h, range: 7.0-41.5 h;) compared to DX (PlCl: 56.8 l/h, range: 24.4-119.5; MRT: 45.6 h, range: 26.0-83.1 h). No statistically significant differences could be detected for the volume of distribution at steady state (Vss) (epiDX, 31.8 l/kg; DX, 33.3 l/kg). Metabolites common to both compounds were detected in plasma: the 13-dihydro derivatives doxorubicinol (DXol) and epirubicinol (epiDXol), together with minor amounts of four aglycones (7-deoxy adriamycinone, adriamycinone, 7-deoxy 13-dihydro adriamycinone, and 13-dihydro adriamycinone). Following epiDX administration, two additional major metabolites were detected: the glucuronic acid conjugates of epiDX (4'-O-beta-D-glucuronyl-4'-epiDX) and epiDXol (4'-O-beta-D-glucuronyl 13-dihydro-4'-epiDX). This additional detoxication route appears to account for the more efficient and faster elimination of epiDX than of DX. In the urine collected in the 6 days after treatment, 12.2% of the DX and 11.9% of the epiDX dose was excreted as unchanged drug and fluorescent metabolites. A comparable renal clearance was calculated for DX (4.7 l/h, range 1.4-7.0 l/h) and epiDX (4.4 l/h, range 1.7-7.0 l/h). One patient with hepatic metastases and abnormal bilirubin serum level had percutaneous biliary drainage because of extrahepatic obstruction. The elimination of both drugs was significantly impaired in this patient; nevertheless, elimination of epiDX was still more efficient and faster than that of DX (PlCl: 35.6 vs. 24.4 l/h; MRT: 39.0 vs. 83.1 h; t/2 gamma: 47 vs. 74 h). This patient's biliary excretion accounted for 35.4% of the epiDX dose and 18.2% of the DX dose.

Medroxyprogesterone acetate plasma pharmacokinetics after intravenous administration in rabbits.

Medroxyprogesterone acetate (MAP) plasma pharmacokinetics was followed up in a total of 30 New Zealand rabbits after i.v. administration (0.1, 0.5, and 1.0 mg/kg) of either an aqueous suspension or a homogeneous solution of the drug in dimethylsulphoxide (DMSO). A well-defined triphasic decay of MAP plasma levels was noticeable in the animals treated with DMSO solutions. A delayed concentration peak was often present when aqueous suspensions were used, so if is not feasible to fit the experiment with simple polyexponential equations. Model-independent pharmacokinetic analysis (statistical moment theory) revealed a significant dependence of plasma clearance and mean residence time on the dose administered in both conditions.

Intrahepatic arterial administration of 4'epidoxorubicin (epirubicin) in advanced cancer patients. A pharmacokinetic study.

Epirubicin (epiDX) pharmacokinetics was followed in 10 advanced cancer patients with hepatic metastases from colorectal carcinoma or primary liver tumor after single bolus administration (20-40 mg) in the hepatic artery, through a surgically implanted catheter and subcutaneous access port. EpiDX plasma and whole blood concentrations follow a triphasic decay qualitatively similar to that observed after IV administration. Blood levels are consistently higher than plasma levels. Plasma clearance (nine patients, mean: 93.4 l/hr; range: 69.3-129.5 l/hr) is higher than the corresponding parameter determined in patients with hepatic metastases after intravenous therapy. The remaining patient is characterised by an abnormally low plasma clearance (13.6 l/hr), due to a hepato-pulmonary shunt. The subjects in this study were exposed to very low drug concentrations, and therefore experienced no relevant adverse side-effects.

Medroxyprogesterone acetate plasma levels after a single oral administration of two drug formulations.

A comparison has been made between the absorption of oral medroxyprogesterone acetate (MPA) in an aqueous suspension preparation and in syrup form. Plasma drug profiles were measured after a single administration of the two formulations in 17 advanced cancer patients. On average the standard form (aqueous suspension) gave peak levels which were lower than the syrup mixture. However, the wide intersubject spread in MPA plasma levels observed in both groups did not allow any statistical significance to be assigned to this difference.

MPA at high doses in advanced breast cancer: a statistical evaluation.

A computerized, retrospective analysis of clinical and pharmacokinetic data relative to 380 cancer patients under medroxyprogesterone acetate (MPA) therapy has been carried out. A bioavailability:objective- response correlation was found only for mammary cancer patients with visceral metastases and a pain-control effect was observed in advanced cancer patients when MPA plasma levels were higher than 150-200 ng/ml. Discriminant analysis of the known prognostic factors for breast cancer indicates that receptorial status, site of predominant metastases, basal alkaline phosphatase and free interval are good predictors for possible clinical response, while the behavior of prolactin and previous treatments are predictors for non-response. There is no improvement in the efficacy of prediction in combining more than one prognostic factor.

Biliary excretion and pharmacokinetics of 4'epidoxorubicin (epirubicin) in advanced cancer patients.

Plasma pharmacokinetics and biliary and urinary excretion of the new doxorubicin analogue, epirubicin, have been studied in three patients with extrahepatic obstruction and percutaneous biliary drainage. At variance with the reported observations concerning doxorubicin metabolism, conjugation of epirubicin and 13-dihydroepirubicin with glucuronic acid takes place, and corresponding amounts of 4'-o-beta-D-glucuronyl-4'-epidoxorubicin and 4'-o-beta-D-glucuronyl-13-dihydro-4'-epidoxorubicin can be found in the bile and urine. The total amount of unaltered drug and metabolites excreted in the bile in the first 4 days after treatment accounts for the 37%, 27%, and 40% of the administered dose; urinary excretion accounts for 19%, 16%, and 26%. Biliary clearance of epiDX (32.5, 8.1 and 21.6 l/h) is higher than renal clearance (15.2, 3.3 and 9.41 l/h). The relevance of the biliary disposition of epirubicin suggest prudent dose reduction in patients with impaired biliary drainage.

Low dose oral administration of 4-demethoxydaunorubicin (idarubicin) in advanced cancer patients. A pharmacokinetic study.

Data relating to 4-demethoxydaunorubicin (DMDR) pharmacokinetics after oral administration (10-15 mg/m2 per day for 3 days) were collected in a total of 12 patients with advanced breast cancer and melanoma. Drug absorption took place in the first 2-4 h after administration. Plasma levels of the reduced metabolite DMDRol were higher than those of the parent compound: Peak levels were 4-10 ng/ml for DMDR and 15-40 ng/ml for DMDRol. The dose-corrected area under the time-concentration curve (AUC) was consequently higher for DMDRol (12.3-74.7, mean 32.6 vs 2.4-7.4, mean 4.6 ng/ml.mg for DMDR). Apparent plasma terminal half-lives after the last dose administered were in the range of 13-36 (mean 23.7) h for DMDR and 30-81 (mean 58.9) h for DMDRol. Drug and the reduced metabolite accumulated in the blood cells; the ratio of AUC (blood) to AUC (plasma) was 1.40-3.75 (mean 2.80) for DMDR and 1.29-3.50 (mean 2.16) for DMDRol. The biliary excretion of the drug and of the fluorescent metabolites was studied in two additional patients with extrahepatic obstruction and percutaneous biliary drainage. In the first 7 days of therapy, biliary excretion (DMDR + DMDRol) accounted for 3.7%-4% of the administered dose. In contrast to our observations with doxorubicin and epirubicin, urinary excretion seems very likely to be more important for this drug than biliary excretion. In these patients urinary excretions were 2.2, 2.9 times (for DMDR) and 1.2, 3.4 times (for DMDRol) the biliary excretion.