Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens

Purpose: Cyclophosphamide and thioTEPA are frequently used simultaneously in high-dose chemotherapy regimens. During a pharmacokinetic study of 31 courses in 20 patients of cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide given in the combination cyclophosphamide–thioTEPA–carboplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was observed immediately after the start of the thioTEPA infusion. A drug-drug interaction was suspected. This putative interaction was investigated in this study. Methods: Possible sequence dependency, due to inhibition of the formation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by altering the sequence of infusion in three patients (four courses) receiving high-dose chemotherapy with cyclophosphamide (1000 or 1500 mg/m² per day), thioTEPA (80 or 120 mg/m² per day) and carboplatin (265 or 400 mg/m² per day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investigated in human microsomes. Results: A striking sequence dependency of the pharmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased C_max (−62%) and AUC (−26%) values of 4-hydroxycyclophosphamide compared to those of thioTEPA administered 1 h after cyclophosphamide. In human microsomes an inhibition of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC₅₀ of 23 μM. No inhibition of the formation of TEPA by cyclophosphamide was observed. Conclusions: ThioTEPA strongly inhibits the bioactivation of cyclophosphamide and this may decrease both efficacy and toxicity. Our results seriously question the practice of the simultaneous continuous infusion of cyclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance. Received: 31 January 2000 / Accepted: 10 April 2000     

Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism

Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Patients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [³¹P]-nuclear magnetic resonance spectroscopy; [³¹P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m² infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d₁ and d₂. Results: (Data are given as mean values for CD and d₁/d₂ of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d₁ of HD, but significantly increased on d₂ of HD (CL: 83 and 78/115 ml/min; P < 0.01 for d₁ versus d₂). The latter was translated into an increase in formation CL of both active (+16.4 ml/min) and inactive metabolites (+17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P < 0.05 for d₁ versus d₂ of HD). Conclusions: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism. Received: 6 February 1998 / Accepted: 17 August 1998     

Phase II study of second-line treatment with high-dose cyclophosphamide in recurrent metastatic breast cancer

 A total of 78 patients with second recurrence or progression of histologically verified breast cancer were treated with single-agent cyclophosphamide given at 2.5 g/m² by i.v. infusion every 3 weeks along with mesna support. All had previously been treated with epirubicin and cisplatin or epirubicin alone. Toxicity was predominantly hematologic: WHO grade III+IV toxicity was found in 95% of cases. The overall response rate was 26.7% (95% confidence limits, 15.8–41.4%), with 7% of patients achieving a complete response (CR) and 19.7%, a partial response (PR). The median duration of CRs and PRs was 11 and 5 months, respectively. The response rate observed for patients previously treated with epirubicin alone was 30.5% in contrast to the 8.3% recorded for patients previously treated with cisplatin plus epirubicin. Thus, an indication of cross-resistance was absent between cyclophosphamide and epirubicin but possible between cyclophosphamide and cisplatin. Received: 10 January 1995/Accepted: 6 June 1995     

高剂量表阿霉素治疗进展期和晚期乳腺癌

目的评价高剂量表阿霉素（ＨＤ－ＥＰＩ）合并环磷酰胺（ＣＴＸ）、氟脲嘧啶（５－Ｆｕ）治疗进展期和晚期乳腺癌的安全性和有效性。方法对３２例可评价的Ⅲ、Ⅳ期乳腺癌患者静脉给予ＣＴＸ６００ｍｇ／ｍ２、ＥＰＩ９０ｍｇ／ｍ２～１１０ｍｇ／ｍ２、５－Ｆｕ９００ｍｇ／ｍ２,每２１天重复。并与３０例非同期低剂量组比较（ＥＰＩ为５０ｍｇ／ｍ２）。结果高剂量组的总有效率为７１．９％,完全缓解率为１２．５％,明显高于低剂量组（５６．７％和６．７％）;初治的有效率（８０．０％）略高于复治者（６８．２％）。全组中位缓解期７．４个月,中位生存期１２．５个月。白细胞减少为主要的毒副反应,发生率为８９．５％（６８／７６）,Ⅲ、Ⅳ度分别为２７．６％和１８．４％;胃肠道毒性为轻、中度,未见明显的心肝肾毒性。结论ＨＤ－ＥＰＩ＋ＣＴＸ＋５－Ｆｕ方案治疗晚期乳腺癌安全有效,可在临床进一步试用     

环磷酰胺顺铂联合用药与单一用药药代动力学比较

 [摘要] 目的：研究环磷酰胺顺铂联合用药与单一用药药代动力学差异。方法：利用高效液相色谱法检测顺铂和环磷酰胺药代药力学参数和组织分布参数。结果：CP方案的药动学曲线呈二室模型,两药的吸收半衰期,与单一用药无显著性差别（P＞0.05）;而消除半衰期与单一用药相比明显延长,存在显著性差异（P＜0.01）。结论：联合用药时体内消除速度较慢,提示临床应根据药代药力学参数调整给药间隔和用量,才能提高疗效,降低副作用。     

Carbamazepine induces bioactivation of cyclophosphamide and thiotepa

Purpose  We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide [1,000 mg/(m² day)], thiotepa (80 mg/(m² day) and carboplatin (dose calculated based on modified Calvert formula with 3.25 mg min/ml as daily target AUC) over 4 days, followed by peripheral blood progenitor cell support. During the first two cycles the patient concomitantly used carbamazepine for the treatment of epilepsy. Due to severe nausea and vomiting the patient was unable to ingest carbamazepine; therefore, this was discontinued after the second cycle. Methods  Blood samples were drawn on 2 days (day 1 and 2, 3 or 4) of each cycle and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Results  Exposure to 4-hydroxycyclophosphamide and tepa on day 1 was increased in the presence of carbamazepine (58 and 75%, respectively), while exposure to cyclophosphamide and thiotepa was reduced (40 and 43%, respectively). Conclusion  Since increased exposure to the active metabolites is associated with an increased risk of toxicity, it is important to be aware of this drug–drug interaction.     

Epirubicin-containing high-dose chemotherapy followed by autologous hematopoietic progenitor cell transfusion for patients with chemotherapy-sensitive metastatic breast cancer: results of 5-year follow-up

Purpose: Conventional chemotherapy for metastatic breast cancer results in very few long-term survivors. With a view to overcoming this problem, we hypothesized that a higher rate of complete response (CR) would lead to more long-term survivors. Therefore, we conducted a phase II study of epirubicin-containing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell transfusion in patients who were sensitive to induction chemotherapy. Methods: The induction chemotherapy consisted of doxorubicin 60 mg/m², cyclophosphamide 750 mg/m² and fluorouracil 750 mg/m² on day 1. Supported by G-CSF, this chemotherapy was repeated for at least three cycles at intervals of 2 weeks until the achievement of >50% tumor regression. The HDC comprised epirubicin 120 mg/m² on day 1, cyclophosphamide 60 mg/kg on days 1 to 3 and thiotepa 6 mg/kg on days 1 to 3, followed by autologous bone marrow transplantation and peripheral blood stem cell transfusion. Results: Of 25 patients who achieved a partial response to the induction chemotherapy, 17 were treated with the HDC. Of the 15 patients evaluable for response, 10 achieved a CR (67%), giving an overall CR rate of 43% (10/25). The disease-free survival rate at 5 years was 27%. The median duration of overall survival was 21 months and the overall survival rate at 5 years was 31%. However, the survival curves were not significantly different from those of the historical controls who achieved a CR or PR to conventional chemotherapy. There were three early deaths, one as a consequence of disease progression and two treatment-related (sepsis and heart failure). Diarrhea (grade 3, 76%) and stomatitis (grade 3–4, 29%) were the dose-limiting toxicities. Conclusions: The present study suggests that epirubicin-containing HDC is able to induce a high rate of CR, but its benefit in terms of survival is still unclear. To determine whether HDC can achieve a cure in some patients, further studies in a larger number of patients, with a longer follow-up, are necessary. Received: 23 February 1998 / Accepted: 13 May 1998     

Pharmacokinetic and pharmacodynamic analysis of combined chemotherapy with carboplatin and cyclophosphamide in patients with gynecological cancers

Background. This study was conducted to assess the utility of pharmacokinetic and pharmacodynamic analyses of chemotherapy with carboplatin (CBDCA) and cyclophosphamide (CPA). Methods. The pharmacokinetics (PK) and pharmacodynamics (PD) of chemotherapy with CBDCA and CPA were analyzed in 14 patients (12 with ovarian cancers and 2 with uterine cancers). The PD model based on myelosuppression was assessed in terms of concentrations of free platinum (free-Pt) and total CPA in blood samples. CBDCA (300 mg/m²) was administered intravenously (iv) over 1 h, and CPA (500 mg/m²) over 2 h. Free-Pt and CPA concentrations in blood samples were measured at several time points thereafter. Results. The nadirs of leukocyte and platelet counts were closely correlated with the free-Pt concentration 24 h after infusion (Pt-24), and with the CPA concentration 5 h after infusion (CPA-5). A PD model corresponding to the nadirs of leukocyte and platelet counts was thus generated. Conclusion. This PD model allowed ready prediction, from Pt-24 and CPA-5, of the degree of myelosuppression, a dose-limiting toxicity, for combined CBDCA and CPA chemotherapy. Received: June 19, 1997 / Accepted: July 27, 1998     

Lacrimal duct stenosis and other ocular toxicity associated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer

Certain side-effects of chemotherapy are well recognized but ocular toxicity is often underestimated. This retrospective study was undertaken after we became aware of a case of irreversible lacrimal duct stenosis in a woman receiving adjuvant chemotherapy for early stage breast cancer. Using the chemotherapy records, 128 patients who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer over a 2 1/2-year period were identified. The case notes of these patients were reviewed and an 18% incidence of ocular side-effects, including four other cases of epiphora, was identified. The epiphora resolved fully on completion of chemotherapy in these four patients but not in the index patient. The optimal management of these side-effects is unclear but it needs to be tailored to the particular toxicity experienced by the patient.     

New strategies in marrow purging for breast cancer patients receiving high-dose chemotherapy with autologous bone marrow transplantation

Summary High-dose chemotherapy and autologous bone marrow transplantation (ABMT) are commonly used to treat selected patients with high-risk breast cancer. A limitation of ABMT is that clonogenic cancer cells could be collected with the bone marrow and produce a relapse of disease when reinfused into patients. Purging the marrowex vivo may eliminate the tumor cells, but it can also delay engraftment. We employed two different purging methods whereby breast cancer cells were depleted without delaying engraftment. The addition of WR-2721 (amifostine) to 4-hydroperoxycyclophosphamide (4-HC) reduced the time to engraftment by 10 days compared with marrow purged with 4-HC alone (26 versus 37 days, respectively). The positive selection of CD34+ hematopoietic progenitors produced engraftment within 21 days. The use of granulocyte colony-stimulating factor (G-CSF) accelerated the engraftment time of CD34+ hematopoietic progenitors to 11 days.Held in conjunction with the 15th Annual San Antonio Breast Cancer Symposium, December 1992, and supported by an educational grant from Lederle Oncology; editing by The Medicine Group USA, Inc.     

Combination chemotherapy and high-dose cyclophosphamide intensification for poor prognosis breast cancer. A Southwest Oncology Group Study

Thirty-seven patients with poor prognosis, metastatic breast cancer were treated with 5-fluorouracil, vinblastine, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (FUVA) induction chemotherapy. All 26 patients (74%) with responsive or stable disease after induction chemotherapy received intensification with high-dose cyclophosphamide (120 mg/kg). Continued responders received additional FUVA as consolidation. The response rate to induction therapy was 54% (with complete response [CR] in 11%). With intensification, three patients (11%) showed improved response (partial response [PR] in one, PR to complete response [CR] in two); however, six patients (23%) progressed within 2 months of cyclophosphamide intensification, three within 1 month. The overall response rate to all three phases of the study was 69%, with CR in 23%. The median survival of all patients entered in this study was 15 months. For cyclophosphamide intensification, major toxicity consisted of leukopenia with fever requiring broad-spectrum antibiotics in 27%. The authors conclude that a single cycle of high-dose cyclophosphamide intensification in metastatic breast cancer does not result in significantly improved responses or prolonged survival.     

Accelerated chemotherapy with high-dose epirubicin and cyclophosphamide plus r-met-HUG-CSF in locally advanced and metastatic breast cancer

BACKGROUND: This study evaluated the toxicity of high-dose epirubicin andcyclophosphamide plus r-met-HUG-CSF (G-CSF) given every 2 weeksand compared the dose-intensity achieved with this schedulewith that obtained in a previous study we conducted in whichthe same regimen was given every 3 weeks without G-SCF (EC 21).The secondary objective was to explore the activity of thisregimen. PATIENTS AND METHODS: Between December 1991 and March 1994, 41 patients (pts), 19with locally advanced breast cancer (LABC) and 22 with metastaticbreast cancer (MBC), were given high-dose epirubicin (Hd-Epi)(120 mg/m²) and cyclophosphamide (CTX) (600 mg/m²) on day 1every 14 days (EC 14) plus granulocyte colony-stimulating factor(G-CSF) (5 µg/kg/d s.c. on days 2–12). A total of8 cycles in LABC pts (4 pre- and post-surgery), and 6–8cycles in MBC pts were administered. The results were comparedwith those obtained in the previous study. RESULTS: The incidence of WHO grade 3–4 neutropenia was significantlyreduced in te EC 14 + G-CSF regimen (25.2% vs. 46.8% in 214and 250 evaluable cycles, respectively, p< 0.0001), as wellas the incidence of neutropenic fever (7% vs. 3%, p = 0.05).Grade 3–4 anemia (36.6% vs. 8% pts, p = 0.001) and grade3–4 thrombocytopenia (17.1% vs. 0 pts, p — 0.002),were significantly more frequent in EC 14 +G-CSF. No significantdifferences in the other side effects were found.A total of17 of 207 of the cycles (8.2%) were delayed in the EC 14 + G-CSFvs. 58/271 (21.4%) in the EC 21 (p< 0.0001). The main reasonsfor these treatment delays were neutropenia (1% vs. 15%), anemia(3% vs. 0) and thrombocytopenia (1% vs. 0).As a result of treatmentacceleration and differences in dose delays, the patients onEC 14 + G-CSF received a higher dose-intensity (Epi 58.51 mg/m2/wkvs. 36.8 mg/ m7wk; CTX 292.52 mg/m2/wk vs. 182.9 mg/m2/wk).A complete response at surgery was obtained in 9/19 (47.4%)LABC pts. An objective CR was obtained in 11/22 MBC pts (50%)and a partial response in 8/22 (36.4%), yielding an verall responserate of 86.4%. CONCLUSIONS: Hd-Epi + CTX is very active against both LABC and MBC. The administrationof G-CSF allows dose intensification of both drugs (a 59.5%increase of the actual dose intensity) with acceptable clinicaltolerance (a lower incidence of neutropenia but a higher incidenceof anemia and thrombocytopenia). Only a specifically designedphase III trial will lead to definitive conclusions regardingthe greater antitumor activity of accelerated CSF-includingregimens as compared to standard chemotherapy for advanced breastcancer. advanced breast cancer, dose intensity, high-dose epi, rh G-CSF     

Oral UFT and cyclophosphamide combination chemotherapy for metastatic breast cancer

BACKGROUND: Effective long-term chemotherapy yielding good quality of life is essential. The clinical benefits of oral UFT and cyclophosphamide (CPA) combination chemotherapy for metastatic breast cancer (MBC) were evaluated. PATIENTS AND METHODS: Twenty cases with MBC were enrolled. The mean age was 54 years. Five cases had loco-regional and others had distant metastasis. Nineteen cases had previous therapies. Daily treatment consisted of UFT (300 to 400 mg/body) and CPA (100 to 150 mg/body), both given orally. RESULTS: The treatment period ranged from 4 to 80 weeks. The response rate was 35%, while it was 65% in the "stable disease > 6 months" category. The mean time to the first sign of response was 7 weeks and the time to tumor progression was 37 weeks. The frequent adverse effects were leukocytopenia (55%) and gastrointestinal symptoms (35%). The incidence of adverse grade > or = 3 effects was 25%. CONCLUSION: Oral UFT and CPA combination chemotherapy may be suitable for MBC.     

Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency

Purpose  We report a patient with renal insufficiency (creatinine clearance, CL_cr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m² day⁻¹), thiotepa (120 mg/m² day⁻¹) and carboplatin (AUC = 5 mg min/mL day⁻¹) for four consecutive days. Methods  Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined. Results  Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%. Conclusion  These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insufficiency.     

Efficacy and toxicity of vinorelbine with doxorubicin/cyclophosphamide combination chemotherapy in a phase I-II study for advanced or recurrent breast cancer patients

BACKGROUND: To evaluate the efficacy and toxicity of vinorelbine (VNB) with doxorubicin/cyclophosphamide (AC) combination chemotherapy, a phase I-II study was carried out in patients with advanced or recurrent breast cancer. METHODS: The phase I part of this study was carried out to determine the treatment schedule and acceptable dose of VNB for the phase II study. In phase I, VNB was initially given as a short infusion on days 1, 8 and 15, every 4 weeks. The initial dose of vinorelbine was 15 mg/m2. In the AC regimen, 20 mg/m2 of doxorubicin (ADM) was given intravenously (i.v.) on days 1 and 8, and 100 mg/body of cyclophosphamide (CPA) was administered orally from days 1 to 14. Subsequently, a phase II study was carried out at the maximum acceptable dose (MAD). RESULTS: Twenty-three patients were entered into this study. In patients receiving VNB at a dose of 15 mg/m2, neutropenia (> or = grade 3) frequently occurred on day 15. The treatment schedule of this study was therefore changed to VNB given i.v. on days 1 and 8 with AC combination chemotherapy. In this treatment schedule, grade 4 neutropenia lasting for more than 4 days occurred in patients given VNB at a dose of 20 mg/m2 with AC more frequently than in those given 15 mg/m2 of VNB. Therefore, the MAD of VNB was determined to be 20 mg/m2 in this regimen. At this recommended dose, there were 1 complete (CR) and 8 partial responses (PRs) in 15 patients, with an overall response rate of 60.0%. No treatment-related death occurred. CONCLUSIONS: These data indicate that VNB plus AC combination chemotherapy was effective and well tolerated for breast cancer patients. A randomized trial of VNB plus AC vs. AC combination chemotherapy may be required to ascertain the benefit of this regimen for advanced or recurrent breast cancer patients.     

Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer.

Fifty-five consecutive women with advanced breast cancer were treated with a combination of adriamycin (40 mg/m2 administered intravenously on day 1) and cyclophosphamide (200 mg/m2/day given orally in divided doses for 4 days on days 3-6). Courses were repeated at 21-28-day intervals. The mean age for the 55 patients was 55 years (range, 37-77 years); 20% of the patients were 65 years or older. All patients were evaluable. Objective response (at least a 50% decrease in the size of all measurable lesions lasting for at least 1 month) was noted in 40 (80%) of the 50 patients who received an adequate trial of chemotherapy (a minimum of two courses). Six of the 40 responses observed were complete. The median duration of response was 10 months. Actuarial survival for the entire group of 55 patients was 80% at 6 months after initiating chemotherapy and 70% at 12 months. Survival for the 40 responding patients was 95% at 6 months and 80% at 12 months. Response rates by site of involvement were: soft tissue, 20/25 (80%); lymph node, 15/19 (79%); bone, 21/25 (84%); lung, 15/18 (83%); pleural effusion, 6/8 (75%); and liver, 7/10 (70%). Eighty-three percent of the responses were apparent after two courses of treatment and 98% were apparent after four courses. Toxicity was acceptable and included nausea, myelosuppression, alopecia, and reversible congestive heart failure (in 2 patients who received 550 mg/m2 of adriamycin). Chemotherapy with adriamycin and cyclophosphamide proved to be safe and effective for out-patient treatment of advanced breast cancer.     

Pharmacokinetics of cyclophosphamide and its metabolites in paediatric patients receiving high-dose myeloablative therapy

Introduction

In order to better understand the impact of high-dose on the pharmacokinetics and metabolism of cyclophosphamide, a pharmacological study was performed in children with malignant mesenchymal tumours with metastatic disease.

Methods

Patients received four courses of chemotherapy including two courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and the metabolites 4-ketocyclophosphamide, dechloroethylcyclophosphamide and carboxyphosphamide were determined on days 1, 2 and 3 of each course. A population pharmacokinetic model for cyclophosphamide was developed using non-linear mixed effects modelling and metabolite AUC values were compared between days and courses.

Results

Data were available on 21 cyclophosphamide courses from 15 patients. A one compartment model, incorporating a term in surface area for both CL and V, best described cyclophosphamide pharmacokinetics. Typical CL and V on day 1 of treatment for a patient with a SA of 1.4 m² were 4.3 L/h and 28.5 L, respectively. On days 2 and 3 CL increased by 88% (95% CI, 72-105%) and 125% (95% CI, 108-145%) over day 1 levels; V increased by 14% (95% CI, 5-23%) on days 2 and 3. V tended to be larger for males than similarly sized females but no effect of age was found upon CL or V. Significant increases in metabolite AUCs were observed on days 2 and 3 compared to day 1 and a significant increase in CXCP AUC from course 1 to course 3.

Conclusion

Administration of high-dose cyclophosphamide over several days results in an increase in metabolism, possibly by induction of the activation pathway. This induction is effectively reversed following a four week period between cyclophosphamide doses. The degree of intersubject variation in cyclophosphamide elimination is largely accounted for by body surface area and is less than previously reported.     

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer

BACKGROUND: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer. METHODS: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day. RESULTS: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks. CONCLUSION: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.