A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers

PURPOSE: The aims were to determine the maximum tolerable dose (MTD) of docetaxel with CYP3A inhibition by ketoconazole, and to correlate the pharmacokinetics of docetaxel with midazolam phenotyping of CYP3A activity. METHODS: Forty-one patients with refractory metastatic cancers were treated with an escalating dose of intravenous docetaxel once in every 3 week of 10 mg/m(2), concurrently with oral ketoconazole 200 mg twice daily for 3 days starting 2 days before the administration of docetaxel. Midazolam phenotyping test with ketoconazole modulation was performed before the first cycle of docetaxel. Docetaxel and midazolam pharmacokinetics were compared to our previous study of docetaxel treatment without ketoconazole modulation. RESULTS: Neutropenia was the dose-limiting toxicity. The maximum tolerated dose was 70 mg with mean AUC at 70 mg similar to 75 mg/m(2) of docetaxel without ketoconazole. The plasma clearances of docetaxel and midazolam were reduced by 1.7- and 6-fold, respectively. The variability of midazolam AUC was reduced from 157 to 67%, but variability of docetaxel clearance was not reduced by CYP3A inhibition. Docetaxel clearance correlated with renal function and maximum concentration of ketoconazole, but not midazolam clearance or other variables of hepatic function. CONCLUSION: Fixed dosing was found to be feasible, without increased variability of clearance or neutrophil toxicity compared to BSA-based dosing. With ketoconazole modulation, docetaxel clearance correlated with renal function but not CYP3A phenotype.     

Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects

The study under discussion was a drug–drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib C_max, AUC_(0–24) and AUC_(0–) increased significantly by 26% (P<0.005), 40% (P<0.0005) and 40% (P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% (P<0.0005). The mean C_max and AUC_(0–24) of the metabolite CGP74588 decreased significantly by 22.6% (P<0.005) and 13% (P<0.05) after ketoconazole treatment, although the AUC_(0–) of CGP74588 only decreased by 5% (P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.     

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.     

Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma

Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n= 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17–95%)] and clearance [CL, 1.1 (0.7–2.3) l h⁻¹ m⁻²] resulting in a normal degree of systemic exposure (AUC_oral 27 μg h ml⁻¹). Normal protein binding [PB 93.2% (84.4–98.1%)] contributed to a normal level of exposure to free drug (AUC_{f, oral} 1.9 μg h ml⁻¹). The distribution volume [V_SS 8.4 (6.1–13.2) l/m²] and the effective half-life [t _1/2eff, 5.1 (3.0–9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of >1.2 mg/dl as compared with the ten patients with total bilirubin levels of ≤1.2 mg/dl (1.3 versus 1.0 l h⁻¹ m⁻² and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring. Received: 11 May 1998 / Accepted: 5 August 1998     

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     

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     

异环磷酰胺、鬼臼乙叉甙、卡铂方案治疗晚期非小细胞肺癌的疗效观察

目的：观察异环磷酰胺、鬼臼乙叉甙、卡铂（IEC）方案治疗晚期非小细胞肺癌的疗效和毒副反应。方法：33例晚非小细胞肺癌患者接受IEC方案化疗。观察全组患者的近、远期疗效及毒副反应。结果：全组患者PR7例，NC24例，PD2例，有效率为21．2％（7／33，95％CI：7．3％－35．1％）；中位生存期7．8月（95％CI：6．2－9．4月）；1年生存率为20．0％（95％CI：6．0％－34．0％）。主要毒副反应为较严重的血液学毒性，Ⅲ-Ⅳ度白细胞减少、血少板减少及血红蛋白减少发生率分别为51．5％（17／33）、18．2％（6／33）和30．3％（10／33）。60岁以上组Ⅲ-Ⅳ度白细胞减少发生率（P＝0．024）和血小板发生率（P＝0．037）明显高于60岁以下组。结论：IEC方案对晚期非小细胞肺癌有效；主要毒副反应为较严重的血液毒性，尤其高发于老年人，因此对于老年患者最好在G－CSF或GM－CSF的支持下进行治疗。     

Phase I and pharmacologic study of 7- and 21-day continuous etoposide infusion in patients with advanced cancer

 Purpose. This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. Methods. A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m² per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m² per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC) were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between variables. Results. Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia was 75 mg/m² per day for schedule A and 40 mg/m² per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was ≥1 μg/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r=0.56,  P=0.003). There were several marginal relationships in schedule B: PS versus Css (r=0.31,  P=0.058), PS versus AUC (r=−0.38; P= 0.058) and age versus CLp (r=−0.31, P=0.057). Conclusion. Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice is the presence of significant interpatient variability. Received: 3 April 1995/Accepted: 6 December 1995     

CPE和CE方案治疗小细胞肺癌的疗效比较

目的　评价CPE(卡铂、顺铂、足叶乙甙)和CE(卡铂、足叶乙甙)方案治疗小细胞肺癌(SCLC)的疗效和毒性。方法　应用CPE和CE方案治疗32例SCLC患者,每组16例,CPE组和CE组中的复治病例分别为10例和7例。结果　CPE组和CE组的有效率分别为81.3%(13/16)和87.5%(14/16)(P>0.05)。CPE组与CE组中的复治病例有效率分别为60%(6/10)和42.9%(3/7)(P<0.05)。CPE组与CE组的骨髓抑制率分别为71.9%和93.8%(P<0.05)。两组间其它毒性反应差异无显著性(P>0.05)。结论　CPE方案治疗SCLC的疗效与CE方案相近,但CPE的骨髓抑制明显较CE轻;CPE对复治病例的疗效优于CE。     

Biliary excretion of etoposide in children with cancer

Purpose: Two children with soft tissue sarcomas receiving etoposide as part of their standard clinical treatment had external biliary drainage due to obstruction of the bile duct. These unusual cases provided an opportunity to investigate the biliary clearance of etoposide by determining etoposide concentrations in bile and plasma samples obtained during chemotherapy. Patients and methods: Etoposide was administered to patient 1 at a dose of 150 mg/m², as a 4 h infusion, on each of three days of treatment. Patient 2 received a daily etoposide dose of 800 mg/m² as a 24 h continuous infusion, also over a 3-day treatment period. Bile and plasma samples were obtained at regular intervals from both patients and etoposide levels quantified by LC/MS analysis. Results and discussion: Biliary etoposide clearance was approximately equal to the flow of bile, with an average clearance of 0.32 ml/min determined in patient 1. Less than 2% of the etoposide dose administered was excreted in the bile in either patient studied, indicating that biliary clearance of etoposide is relatively minor. These results suggest that etoposide dose adjustment is unnecessary in patients with biliary obstruction.     

Second-line chemotherapy with long-term low-dose oral etoposide in patients with advanced breast cancer

Summary In a phase II study, 27 patients with metastatic breast cancer were treated with oral etoposide as second-line chemotherapy at a dose of 50 mg/m²/day for 21 days, which courses were repeated every 4 weeks. Twenty-one patients were evaluable for response, and twenty-five for toxicity. In two (10%) patients a partial response was observed with a duration of 60 and 122 weeks respectively, and seven patients (33%) showed stable disease. Gastrointestinal toxicity was usually mild, though relatively frequent. Anemia grade II and III was observed in 20% of all courses (< 10% of all measurements), and leukopenia grade III and IV was observed in 22% of all courses (< 10% of all measurements). There was one toxic death.Reviewing the literature we calculated a response rate of intravenous etoposide treatment of 8% in 276 patients with metastatic breast cancer from 7 studies (response rates ranging between 0–14%), while (chronic) oral treatment caused a response rate of 19% in 145 patients from 8 different studies (response rates ranging between 0–35%).     

A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients

Etoposide (VP16), a widely used anticancer drug, is a topoisomerase II inhibitor. A number of studies have highlighted a correlation between hematologic toxicity and pharmacokinetic or physiological parameters. Other studies have also suggested that the anti-tumor response could be related to the plasma etoposide concentration. Therefore, it would seem of interest to individualize VP16 dose regimens on the basis of pharmacokinetic parameters. The aim of this study was to develop and validate a limited-sampling strategy allowing VP16 pharmacokinetic evaluation with minimal disturbance to the patient. A total of 34 patients (54 kinetics) received VP16 at various dose regimens, with doses ranging between 30 and 200 mg and infusion times varying between 0.5 and 2 h. The statistical characteristics of the pharmacokinetic parameters were assessed from the first courses of treatment performed in 23/34 patients; then the following three-sample protocol was designed: the end of the infusion and 5 and 24 h after the start of the infusion. For validation of the model the main pharmacokinetic parameters (clearance, half-lives, volume of distribution) were estimated in the 11 remaining patients by maximum-likelihood estimation (ML) and by Bayesian estimation (BE) using the three sampling times designed. Statistical comparison showed a good concordance between ML and BE estimates (the bias for clearance was –1.72%). The limited-sampling strategy presented herein can thus be used for accurate estimation of VP16 pharmacokinetic parameters. Received: 17 November 1997 / Accepted: 25 August 1998     

Pharmacokinetic study of weekly administration dose of paclitaxel in patients with advanced or recurrent gastric cancer in Japan

Background We aimed to clarify the relationship between the maximum tolerated dose and plasma concentration of paclitaxel in Japanese patients with gastric cancer on a weekly paclitaxel administration regimen. Methods Thirty-three patients with advanced or recurrent gastric cancer were treated with escalating doses of paclitaxel, administered weekly, along with a fixed dose of 5-fluorouracil or cisplatin. Results The plasma concentration of paclitaxel remained above 8.5 ng/ml for 24 h after administration. The mean area under the curve increased significantly with escalating dosage levels (R = 0.63; P 0.001). At level 4, patients showing dose-limiting toxicity had a significantly higher plasma paclitaxel concentration than patients without it. Conclusion The weekly administration of paclitaxel, for which a single dose is about one-third of the dose for a tri-weekly treatment regimen, is clinically feasible and appropriate in terms of toxicity and the maintenance of an effective plasma concentration.     

Pharmacokinetics of oral O6-benzylguanine and evidence of interaction with oral ketoconazole in the rat

Purpose: O⁶-Benzylguanine (BG) is a modulator of the DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (AGT). BG is converted in mice, rats and humans to an equally active, yet longer-lived metabolite, O⁶-benzyl-8-oxoguanine (8-oxo-BG) by CYP1A2, CYP3A4 and aldehyde oxidase. Since intravenous BG is expected to enter phase I development with orally administered anticancer agents such as temozolomide, procarbazine or SarCNU, we determined the bioavailability of orally administered BG, as well as the effect of ketoconazole, a potent intestinal and hepatic CYP3A4 inhibitor, on the disposition of BG. Methods: Following intravenous or oral administration of BG in PEG-400/saline (40:60) to Sprague-Dawley rats, the pharmacokinetics of BG and 8-oxo-BG were determined. To determine the effect of CYP3A inhibition on disposition, oral BG was coadministered with ketoconazole. Results: The peak plasma concentration (C_max), time to C_max (t_max), and bioavailability (F) of oral BG were: 2.3 ± 0.9 μg/ml, 2.3 ± 0.6 h, and 65.5% respectively. The AUCs of BG and 8-oxo-BG were 13.1 ± 4.6 μg · h/ml and 1.7 ± 0.4 μg · h/ml after oral administration of BG. Coadministration with ketoconazole resulted in an increase in mean absorption time from 2.0 ± 0.3 h to 6.0 ± 0.9 h, a shift in t_max to 5 ± 3.3 h, a decrease in C_max to 0.96 ± 0.8 μg/ml, and a decrease in AUC_0-inf ratio of 8-oxo-BG:BG from about 0.12 to 0.04 (P < 0.05). The bioavailability of BG was not changed (65.5% vs 56.9%, P=0.78). Conclusions: The oral bioavailability of BG is high, warranting consideration of an oral formulation for clinical development. Coadministration of ketoconazole and BG resulted in delayed oral absorption and inhibition of conversion of BG to 8-oxo-BG in the rat model. Received: 12 July 1999 / Accepted: 11 February 2000     

Chronic oral etoposide in advanced breast cancer

Chronic oral etoposide has shown activity in some metastatic refractory tumors. To test its activity in previously treated metastatic breast cancer patients, we started a study in 18 consecutive patients given etoposide orally at 50 mg/m² daily for 21 days. A partial response was observed in 4 of 18 patients (22%); of the responding patients, 3 had visceral metastases and 1 had multiple bone metastases. Leukopenia of grade 3 or 4 was the main hematological toxic effect (23% of patients) and alopecia was the most important nonhematological toxicity. Chronic oral etoposide shows some activity in pretreated patients with metastatic breast cancer, with tolerance being good and toxicity, acceptable. Further studies of this drug given as first-line chemotherapy or in combination with other drugs can establish all its potential activity in this cancer.     

Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours

 Purpose: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. Methods: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m²) were administered in combination with etoposide 100 or 120 mg/m², and fixed dose of cisplatin 20 mg/m² and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II–V. Results: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m² dose level (II) was 7.0 ± 3.6 h μmol⁻¹ l⁻¹, for the 175-mg/m² dose level (III) 10.6 ± 2.8 h μmol⁻¹ l⁻¹, for the 200-mg/m² dose level (IV) it was 16.0 ± 5.0 h μmol⁻¹ l⁻¹, and for the 175-mg/m² dose level (V) it was 12.5 ± 6.1 h μmol⁻¹ l⁻¹. The mean peak plasma concentration (C_max) values for dose levels II–V were 1.9 ± 1.1 μmol/l, 3.4 ± 1.2 μmol/l, 4.3 ± 1.0 μmol/l and 3.8 ± 1.2 h μmol/l, respectively. Conclusion: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C_max and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-μmol/l threshold concentration (t > 0.1 μM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded. Received: 29 June 1998 / Accepted: 29 January 1999     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

Vincristine with high-dose etoposide in advanced breast cancer: a phase II trial of the Piedmont Oncology Association

Vincristine (VCR) and etoposide (VP-16) have been shown to be synergistic in a murine model, and this combination was studied in a phase II trial. Eligibility required measurable disease, a performance status of 0–2, a life expectancy of 2 months, an interval of at least 3 weeks since the receipt of previous radiation therapy or chemotherapy and recovery from related toxicity, no prior treatment with VCR or VP-16, and no more than two prior chemotherapy regimens (only one for treatment of metastatic disease). Treatment consisted of 0.5 mg i.v. (bolus) VCR followed by 200 mg/m² VP-16 given over 2 h. Both drugs were given daily for 3 consecutive days every 3 weeks (total dose: VCR, 1.5 mg; VP-16, 600 mg/m²). A total of 18 patients with metastatic breast cancer were accured; 14 had adjuvant chemotherapy and 8 had chemotherapy for advanced disease. As judged by International Union Against Cancer (UICC) criteria, one complete response (CR) and three partial responses (PR) were obtained, for a CR+PR rate of 22% (95% confidence interval, 6%–48%). All responders had soft-tissue involvement only. Six patients had stable disease and 8 showed progression. The median time to treatment failure was 3.5 months, and the median survival from study entry was 8.3 months. The major toxicity was myelosuppression, with 9 patients (50%) experiencing a total WBC of <1,000/mm³. Grade 2–3 neurologic toxicity was noted in 6 patients (33%) and grade 3 nausea and vomiting was noted in 5 (28%). The combination of VCR and VP-16 is active in advanced breast cancer but is not convincingly superior to either of these agents used alone.Supported in part by grants CA-12197, CA-37378, and CA-45808 from the National Institutes of Health, National Cancer Institute, Bethesda, Maryland     

Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer

Introduction: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. Patients and Methods: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m²/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. Results: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. Conclusion: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.Two of the co-authors: Edem Agamah (owns shares of Pfizer) and Mark J. Ratain [Co-inventor on several patents (pending/issued) related to the modulation or irinotecan and/or its Pharmacogenetics] would like to declare their potential conflicts of interest.     

A phase I study of prolonged ambulatory infusion carboplatin with oral etoposide showing activity in prostate cancer

Purpose: This phase I study aimed to establish the dose for phase II trials of a dose-intense outpatient regimen of ambulatory carboplatin and oral etoposide. Patients and Methods: Cohorts of three patients received escalating doses of carboplatin 15, 20, and 23 mg/m²/day as a 3-week continuous ambulatory infusion with oral etoposide initially at 50 mg/day. Patients entered had prostate, colon, head and neck, breast, unknown primary cancers and mesothelioma. Results: At 23 mg/m² of carboplatin, two patients had WHO grade 3 lethargy and myelosuppression, which were the dose-limiting toxicities. Six patients were entered at the dose recommended for phase II studies, carboplatin 20 mg/m²/day and etoposide 50 mg/day for 21 days repeated every 6 weeks. This was well tolerated except for one patient with multiple bone metastases from prostate cancer experiencing grade 4 myelosuppression and a single patient with grade 3 constipation. Seven patients with hormone-resistant prostate cancer were entered into the study, one at 15 mg/m², four at 20 mg/m² and two at 23 mg/m² of carboplatin, and received a median of four cycles of treatment. The only responses were seen in prostate cancer where there were two partial responses in patients with soft tissue predominant disease. Five patients who could be evaluated with initially elevated PSA exhibited falls of ≥50% after receiving the chemotherapy. All but one patient with prostate cancer experienced significant reduction in pain levels. The median time to progression of the patients with prostate cancer was 4 months. Conclusions: Ambulatory infusion carboplatin and oral etoposide is a tolerable dose- intense outpatient regimen which warrants further testing in phase II trials including hormone-resistant prostate cancer. Received: 13 March 2000 / Accepted: 26 May 2000