Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients

PURPOSE: To compare etoposide pharmacokinetics following administration of high-dose etoposide and etoposide phosphate, a water-soluble prodrug of etoposide. Bioequivalence was assessed using a two-treatment randomized crossover design. METHODS: Ten patients with high-risk or relapsed lymphoma were treated with a sequential high-dose chemotherapy. They were randomized to receive either 3 x 400 mg/m2 etoposide or an equimolar amount of etoposide phosphate (as 1-h infusions on three consecutive days) in the first course and the alternative drug in the second course. Serial plasma and ultrafiltered plasma samples were collected and analysed for etoposide by a reversed-phase HPLC method with UV and electrochemical detection. Pharmacokinetic parameters were estimated using a two-compartment model. Bioequivalence was assessed calculating the 90% confidence intervals (CI) for the ratios of the geometric means of AUC(0-infinity) and additionally of Cmax of etoposide derived from etoposide phosphate relative to etoposide in plasma and ultrafiltered plasma as point estimates (level of significance alpha < 0.05). RESULTS: Pharmacokinetic parameters of etoposide were comparable in both treatment arms except that terminal half-life was significantly shorter and apparent Vss in ultrafiltered plasma was significantly larger following administration of the prodrug. The point estimates for AUC(0-infinity) of etoposide derived from etoposide phosphate relative to etoposide were 102.9% and 88.4% for plasma and ultrafiltered plasma, respectively. The 90% CIs were in the range from 80% to 125% where bioequivalence can be assumed. The point estimates of Cmax on day 3 of chemotherapy were 96.5% and 81.7% in plasma and ultrafiltrate with the 90% CI in ultrafiltered plasma being out of the range from 80% to 125%. CONCLUSION: With respect to total drug exposure, represented by AUC(0-infinity), high-dose etoposide phosphate is bioequivalent to high-dose etoposide.     

Chronic daily administration of oral etoposide in refractory lymphoma

In a phase II study, 25 patients with previously treated lymphoma received oral etoposide for 21 consecutive days. All patients were considered incurable with standard therapy. Etoposide was administered at 50 mg/m² per day: courses were repeated every 28–35 days, depending on myelosuppression. 15 patients (60%) had partial responses (95% CI 41–77%), while 10 patients had no response. Median time to disease progression was 5 months (range 2–13 months). Oral etoposide was active against indolent and aggressive (intermediate and high grade) lymphomas; however, median time to progression was only 3 months in aggressive lymphoma compared with 8 months in indolent lymphoma. Myelosuppression was the major side-effect; 7 patients (28%) had a leucocyte nadir below 1000/μl during the first course, and 11 patients required dose reduction during subsequent courses due to unacceptable leukopenia. All patients had total alopecia, but other side-effects were uncommon. These results highlight the importance of schedule in the administration of etoposide.     

Prolonged administration of oral etoposide in non-small-cell lung cancer: a phase II trial.

PURPOSE: The trial was undertaken to investigate the activity and toxicity of a prolonged schedule of oral etoposide in the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between March 1989 and August 1990, 25 patients with advanced NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days, repeated every 28 to 35 days. The median patient age was 60 years (range, 38 to 84 years); male:female ratio was 12:13. Eight patients had stage IIIB disease; 17 had stage IV. Seventy-six percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received previous chemotherapy with standard agents; nine patients had received previous or concurrent radiation therapy. Plasma etoposide concentrations were measured to estimate etoposide bioavailability and kinetics. RESULTS: Five of 22 patients (23%; 95% confidence interval [CI], 10% to 43%) had partial responses. Median response duration was 5 months (range, 2 to 6 months). Four of five responders were female. Besides alopecia, which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir during course 1 was 3,200/microL; only four of 69 courses produced a leukocyte nadir less than 1,000/microL. Severe thrombocythemia (less than 75,000/microL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 micrograms/mL. A mean serum etoposide concentration greater than 1 microgram/L was maintained for more than 13 hours; the plasma concentration-time curve (AUC) was estimated to be 90% of that predicted after an identical dose of etoposide given intravenously. CONCLUSIONS: Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patients, chronic oral etoposide is well tolerated, and incorporation into combination regimens should be feasible. Etoposide bioavailability may be increased at lower oral doses.     

Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer

Purpose Etoposide is a widely used cytotoxic drug that is commercially available in both intravenous and oral formulations. High interpatient pharmacokinetic variability has been associated with oral etoposide administration. Various strategies used in the past to reduce such variability have not been successful. Hence, this study was designed to evaluate if pharmacokinetic modulation of oral etoposide with ketoconazole could lead to a favorable alteration of etoposide pharmacokinetics, and to assess the feasibility and safety of this approach. Methods Thirty-two patients were treated with ketoconazole 200 mg daily with an escalating dose of oral etoposide starting at a dose of 50 mg every other day. Pharmacokinetic samples were obtained during the first treatment cycle after the administration of an oral etoposide and ketoconazole dose. Additional baseline pharmacokinetic studies of etoposide alone were performed 4 days prior to the first treatment cycle. Results Dose limiting toxicities were neutropenia and fatigue. Ketoconazole increased the area under the plasma concentration–time curve (AUC) of oral etoposide by a median of 20% (p < 0.005). Ketoconazole did not reduce the interpatient variability in etoposide pharmacokinetics. Pretreatment bilirubin levels correlated with etoposide clearance (Spearman’s r = −0.48, p = 0.008). The maximum tolerated dose was etoposide administered at 50 mg daily and ketoconazole 200 mg qd for 3 of 5 weeks. Conclusions Ketoconazole reduces the apparent clearance of oral etoposide, does not alter its toxicity profile and does not reduce interpatient pharmacokinetic variability. Other methods to reduce the pharmacokinetic variability of oral etoposide are needed.     

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

Background The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin’s lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. Patients and methods We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n = 7; female, n = 3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m² given intravenously on day 1, and 200 mg/m² orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. Results Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3 ± 3.7 vs. 12.0 ± 4.2 μg/ml; P = 0.015). The mean bioavailability of oral etoposide was 58 ± 15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m² intravenous and a 200 mg/m² oral dose of etoposide were 74.0 ± 18.3 and 84.9 ± 29.6 μg h/ml (P = 0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4 ± 10.6% after intravenous infusion versus 35.4 ± 9.4% after oral intake (P = 0.422). Renal clearance was also very similar with intravenous and oral route (18.5 ± 7.4 vs. 16.7 ± 6.6 ml/min; P = 0.546). Conclusion The equivalency of AUC after 200 mg/m² of oral and 100 mg/m² of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.     

Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile.

Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 +/- 18% (mean +/- S.D.) for a 0.1 mg ml-1 prodrug solution and 36 +/- 26% for 0.5 mg ml-1. At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml-1 and 10% at 0.5 mg ml-1. No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 65 degrees C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.     

Fractionated doses of oral etoposide in the treatment of patients with aids-related kaposi sarcoma: a clinical and pharmacologic study to improve therapeutic index

The purpose of this study was to examine the antitumor activity, toxic effects, and plasma pharmacokinetics of fractionated doses of oral etoposide aiming at the achievement of prolonged safe and active plasma drug levels in patients with AIDS-related Kaposi sarcoma (KS). This was designed as a phase II trial in which consecutive patients with progressing AIDS-KS after at least 3 months of active antiretroviral therapy received oral etoposide at the dose of 20 mg/m2 every 8 hours daily for 7 days every 21 days, with the study of its plasma pharmacokinetics. Eligible patients were 18 to 60 years old, with a histopathologically confirmed diagnosis of AIDS-related KS, human immunodeficiency virus-positive test, progressing after at least 3 months of active antiretroviral therapy, World Health Organization (WHO) performance status 0 to 3, New York University staging IIA or greater, no active infection except oral candidiasis, normal bone marrow, liver, and renal function, and who signed an informed consent. Objective tumor responses were evaluated after at least one full treatment course according to a modified WHO criteria, and toxicity was evaluated weekly and graded using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) criteria. For the pharmacokinetic study, plasma was obtained from patients during the first drug administration immediately before and at various time points thereafter. Etoposide was measured after extraction from plasma by a standard high-performance liquid chromatography. Twenty-one patients were accrued for the study, and 18 of them met the eligibility criteria. They were all men, with median age of 36 years old (range: 25-50 years), median WHO performance status 0 (range: 0-3) median CD4+ count (cells/mm3) 67 (range: 8-443), prior AIDS diagnosis in 10 of 18 cases, NYU staging IIA (1 patient), IIB (1), IIIA (7), IIIB (1), IVA (4), and IVB (4) sites of disease: mucocutaneous only (5), mucocutaneous/lymph nodes (5), mucocutaneous/lung (5) and mucocutaneous/lymph nodes/lung (2); and prior cytotoxic treatment in two patients. Seventy-two percent of cases presented some form of toxic effect (NCI-CTC). Leukopenia was documented in 50% of cases, anemia occurred in 61%, whereas thrombocytopenia was documented in 17% of the patients. The main nonhematologic toxicities were nausea and vomiting in 17% of cases and alopecia in 44%. The overall objective response rate was 83%, with 2 complete remissions documented (11%). The median duration of responses was 12 weeks (range: 3-45 weeks). The median t1/2 of etoposide in plasma was 4.11 hours (range: 1.95-9.64), area under the curve was 13.51 microg/h/ml (range: 7.12-24.42), Cmax was 2.17 microg/ml (1.40-4.41), tmax (1.00-2.00), mean residence time 4.62 hours (range: 3.75-5.20 hours), CIt (total clearance) 3.13 l/m2/h (range: 1.49-5.20 l/m2/h), Vd 13.08 l/m2 (range: 6.23-19.65 l/m2), and the median etoposide plasma concentration time greater than 1 microg/ml was 3.69 hours (range: 1.00-6.80 hours). The use of fractionated oral daily doses of etoposide produced significant antitumor activity with manageable clinical toxicity in the individuals with AIDS-KS included in this trial. This more favorable therapeutic index of etoposide could be due to the achievement of more sustained plasma levels of the drug within safe but active concentrations.     

Pharmacokinetics and pharmacodynamics of oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia.

PURPOSE: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy. RESULTS: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for 相似文献   

Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide phosphate (BMY-40481)

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25–110 mg/m²/day for 5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110 mg/m²/day for 5 days every 3 weeks and the dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensitivity reactions. The etoposide phosphate:etoposide area under the plasma concentration versus time curve (AUC) ratio was <1% and the pharmacokinetic parameters for etoposide were within previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide AUC and baseline white blood cell count were significant determinants of leucopenia (model r² = 0.51).     

Pharmacodynamics of three daily infusions of etoposide in patients with extensive-stage small-cell lung cancer

The objectives of this study were to define the pharmacodynamics of etoposide and to develop potentially useful models (1) to estimate the plasma clearance using a limited number of samples and (2) to describe the relationship between clearance and the dose-limiting toxicity. A total of 17 patients with extensive-stage small-cell lung cancer were treated with 150 mg/m2 etoposide daily for 3 consecutive days and with 100 mg/m2 cisplatin on day 3 only. Both drugs were given intravenously over 1 h. Treatment was repeated every 21 days for up to six courses. All patients were newly diagnosed (no previous chemotherapy or irradiation) and had a performance status of 0-2. Six patients achieved a complete response as confirmed by repeat bronchoscopy and five patients showed a partial response, for an overall objective response rate of 65% (95% confidence interval, 38%-87%). The median survival was 8 months (range, 1-24+ months). The dose-limiting toxicity was neutropenia. Etoposide pharmacokinetics were measured during the first course and determinations were repeated during courses 3 or 4 and 6. Complete blood counts were obtained weekly. Correlations for etoposide clearance and hematologic toxicities were evaluated for 17 initial courses and for an overall number of 33 courses. Pharmacodynamic correlations were significant for graded hematologic toxicities, as well as nadirs of leukocytes, neutrophils, and platelets for the initial courses and for all courses. To reduce the requirement for numerous blood samples, a limited sampling model was developed to estimate the area under the concentration versus time curve (AUC) with the following equation: AUC = 15.45 + 3.86 x C2 + 7.10 x C4, where C2 and C4 represent the etoposide concentrations at 2 and 4 h, respectively. The total plasma clearance was calculated as the dose divided by the AUC; correlations with toxicity were better for clearance expressed in milliliters per minute than for that expressed in milliliters per minute per square meter of body surface area. The absolute neutrophil count at the nadir (ANCn) can be estimated by the following pharmacodynamic model, which is based on 33 courses: ANCn = -0.399 + 0.024 x Ecl, where Ecl represents the etoposide clearance expressed in milliliters per minute. Further studies are necessary to validate both models prospectively.     

Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide.

We performed a phase I and pharmacological study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of the novel topoisomerase I inhibitor topotecan in combination with the topoisomerase II inhibitor etoposide, and to investigate the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5 followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day-1)/(mg bid). After encountering DLT, additional patients were treated at 3-week intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and etoposide administration prolonged from 7 to 10 days to allow further dose intensification. Of 30 patients entered, 29 were assessable for toxicity in the first course and 24 for response. The DLT was neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia grade IV that lasted more than 7 days. Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose intensification, as a time delay to retreatment owing to unrecovered bone marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion. Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concentration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stable disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide 40 mg bid on days 6-12 every 4 weeks.     

Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration.

The objective of this study was to accurately determine the within- and between-patient variability in etoposide pharmacokinetics for i.v. and p.o. administered drug. Inter-and intrapatient variability in systemic etoposide exposure was measured following i.v. and p.o. drug administration using stable isotope dilution methodology. Seven patients received 50 mg of etoposide by both p.o. and i.v. routes of administration on three separate occasions 1 month apart. Etoposide plasma concentrations following p.o. and i.v. drug administration were quantitated by liquid chromatography-mass spectrometry for each route of administration. The area under the plasma etoposide concentration versus time curve, plasma etoposide clearance, and etoposide plasma half-life were calculated for each dose of drug. Kinetic measurements following i.v. and p.o. drug administration were compared. The within-patient variation in the areas under the plasma etoposide concentration versus time curves following i.v. drug administration was minimal [coefficient of variation (CV) = 9.3%]. Within-patient variability was increased 2.4-fold with oral drug administration (intrapatient CV = 22.2%). Between-patient variability was roughly three times as great as within-patient variability (interpatient i.v. CV = 28.4%; interpatient p.o. CV = 58.3%). Mean etoposide bioavailability at a dose of 50 mg was 64.6%, again with greater interpatient than intrapatient variability (34.8 versus 22.6%). Greater variation in drug toxicity is expected with p.o. compared with i.v. etoposide use. Administration of repeated doses of etoposide to the same patient should produce less variation in toxicity than between-patient dosing.     

A phase II trial of cisplatin and prolonged administration of oral etoposide in extensive-stage small cell lung cancer.

Etoposide is a schedule-dependent agent with greater activity against small cell lung cancer (SCLC) when a given dose is administered over several days compared with a 1-day administration of the same dose. In an attempt to capitalize on the schedule dependency of etoposide, 22 previously untreated extensive-stage SCLC patients were given cisplatin (100 mg/m2 on day 1) plus 21 days of low-dose, oral etoposide (50 mg/m2/d). Chemotherapy was repeated every 28 days for four cycles. Complete blood counts were monitored weekly, and etoposide was discontinued if either the leukocyte or platelet count dropped below 2000/microliters or 75,000/microliters, respectively. All 22 patients were evaluable for response; 18 had either a complete (9%) or partial response (73%), an overall response rate of 82% (95% confidence interval, 62% to 93%). The median response duration was 7 months, and the median survival was 9.9 months (range, 1 to 17+ months). Sixteen (73%) patients received all planned cycles of etoposide. In Cycle 1 of chemotherapy, the median leukocyte nadir was 2700/microliters (range, 100 to 6300/microliters), and median platelet nadir was 180,000/microliters (range, 51,000 to 397,000/microliters). Life-threatening leukopenia (less than 1000/microliters) was rare (3 of 74 cycles). There were three treatment-related deaths, only one of which was associated with neutropenia. One patient had mild renal insufficiency that resolved after discontinuation of therapy. Alopecia was observed in all patients, but other nonhematologic toxicities were uncommon. A randomized study is necessary to determine if this schedule of cisplatin and etoposide administration is superior to more standard methods. However, these data do not indicate a major survival benefit will be derived from increasing the duration of etoposide administration when used in combination with cisplatin given every 28 days.     

Bioavailability of 50- and 75-mg oral etoposide in lung cancer patients

 This study was designed to determine the bioavailability of etoposide capsules administered orally at doses of 50 and 75 mg. Patients with inoperable or relapsed lung cancer, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were eligible. A group of 17 patients were evaluable, all of whom were 75 years old or less, with an ECOG performance status of 0 or 1. The bioavailability of oral etoposide was determined by measuring the area under the etoposide plasma concentration versus time curve (AUC) on days 1, 10 and 21 during a once-daily regimen of oral administration for 21 consecutive days and comparing the value with the AUC achieved following intravenous administration 1 or 2 weeks after the last oral dose. The bioavailability of 50, 75 and 100 mg oral etoposide was determined in six, nine and two patients, respectively. The mean etoposide bioavailabilities (±SD) of the 50-mg and 75-mg doses were 47±11% and 59±18%, respectively, and of the 100-mg dose in two patients were 51% and 33%, respectively. There was no statistically significant difference in bioavailability between the 50-mg and 75-mg doses. The bioavailability of low-dose oral etoposide was the same as that reported in previous higher dose oral etoposide bioavailability studies and that shown on the package insert supplied by the manufacturer. Improved bioavailability of low-dose oral etoposide was therefore not observed in a population of Japanese patients. Received: 12 January 1995/Accepted: 14 May 1995     

Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors

 Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m² infused over 2 h on days 1 and 2, and G-CSF 5 μg/kg per day starting on day 3 until WBC was ≥10 000/μl. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C_pmax) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T_1/2α of 2.09±0.61 h, and T_1/2β of 5.83±1.71 h. An AUC as high as 1768.50 μg.h/ml was observed at a dose of 1200 mg/m². The total body clearance (TBC) showed an overall mean of 15.72±4.25 ml/min per m², and mean volume of distribution (V_Dss) of 5.64±1.06 l/m². The mean residual time (MRT) for etoposide was 6.24±1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C_pmax and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high- dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C_pmax and AUCs, clearance, terminal T_1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration. Received: 18 July 1995/Accepted: 20 October 1995     

The effect of dose on the bioavailability of oral etoposide: confirmation of a clinically relevant observation

Summary The effect of dose on the bioavailability of oral etoposide was investigated in ten patients with malignant mesothelioma who received single-agent etoposide as part of a phase II study. Etoposide pharmacokinetics were studied in each patient at oral dose levels of 100, 200, 300, 400 and 600 mg. At doses above 200 mg, the AUC and peak concentrations of etoposide were substantially lower than predictions based on the 100-mg dose. This study confirms previous observations that etoposide absorption is dose-dependent and that a mean bioavailability of approximately 50% cannot be assumed at total oral doses >200 mg.     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Prolonged daily administration of oral etoposide in lymphoma following prior therapy with Adriamicin,an ifosfamide-containing salvage combination,and intravenous etoposide

Prolonged daily administration of oral etoposide has been reported to be active in refractory lymphoma. The purpose of this phase II trial was to confirm the activity of this schedule of etoposide in a selected group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). A total of 26 patients (20 with NHL and 6 with HD) were entered in the trial; all had previously been treated with an Adriamycin-based chemotherapy, an ifosfamide-containing salvage combination, and i. v. etoposide. Etoposide was given in a fixed oral daily dose of 100 mg over 3 weeks; the weekly dose (500–700 mg) was selected such that the average daily dose was approximately 50 mg/m². Cycles were repeated on day 29. An objective response was seen in 16 patients (62%; 95% confidence interval, 42%–80%), with a complete response (CR) being observed in 3 cases (12%) and a partial response (PR), in 13 (50%). The median duration of PRs was 3 months. CRs lasted for 15 months in one patient and continue at 12+ and 20+ months in the remaining two patients. The overall actuarial survivial for the entire group was 40% at 2 years; the median survival time was 12 months. The main toxicity was myelosuppression; WHO grade 3 or 4 leukopenia and thrombocytopenia developed in 31% and 12% of the patients, respectively. There was no drug-related death. We conclude that oral etoposide is an effective and tolerable palliative treatment for heavily pretreated lymphoma patients.     

Pharmacological attempts to improve the bioavailability of oral etoposide

Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4±20.3 g ml^–1 h, versus 74.3±25.9 g ml^–1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentrationt _max from 1.1 to 3.5 h (P<0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3±19.1 g ml^–1 h, versus 88.1±23.6 g ml^–1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay int _max being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3–5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.     

A Phase I/II Study of a 72-h Continuous Infusion of Etoposide in Advanced Soft Tissue Sarcoma

Purpose. The study was performed to assess the antitumour activity and toxicity of a 72-h continuous infusion of single-agent etoposide as second-line treatment for patients with locally advanced or metastatic soft tissue sarcoma (STS), following reports of substantial activity using this schedule of etoposide administration as first-line treatment in combination with ifosfamide.Patients/method. This was an open phase I/II trial performed at a single institution in patients with metastatic or locally advanced STS who had failed first-line treatment with doxorubicin + ifosfamide combination chemotherapy or, less commonly, single-agent treatment with doxorubicin or ifosfamide. Etoposide was given as a continuous intravenous infusion over 72 h. The starting dose level was 200 mg m(-2) day(-1) x 3 escalating in 10% steps in cohorts of three patients until dose-limiting toxicity was encountered.Results. Seventeen patients were treated, median age 47 years (range 26-71 years). No responses were seen in 16 assessable patients despite etoposide levels in the cotoxic range. The steady-state plasma concentration exceeded 8 mug ml-(1) in all patients and in patients treated at >/= 600 mg m -(2) the mean steady-state level was 14.4 mug ml -(1). The median event-free survival was 6 weeks (95% confidence interval (CI) 3.31-8.69) and the overall survival 16 weeks (95% CI 9.28-22.72). The maximum tolerated dose in this pretreated patient group was 200 mg mm(-2) day(-1) x 3. The dose-limiting toxicity was myelosuppression.Discussion. Etoposide given by 72-h infusion is inactive as second-line chemotherapy in STS. It is associated with significant toxicity when given in these doses, in this patient group.