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J H Schellens

Publications and source records attributed to J H Schellens.

At least 19 recordsLinked to original sources
PubMed1998

Clinical research on antiangiogenic therapy.

A promising novel target for anti-cancer therapy is the tumour vasculature. Both primary tumour growth and the formation of metastasis depend on the establishment of new blood vessels from preexisting ones, a process called angiogenesis. Inhibition of angiogenesis and targeting of the tumour vasculature are highly effective in controlling tumour growth. Several natural and synthetic compounds have been developed and are currently tested in pre-clinical and clinical studies. This review intends to provide an overview of agents with antiangiogenic activity and the early clinical experience with these drugs.

Antibodies↗
PubMed1998

Abrogated energy-dependent uptake of cisplatin in a cisplatin-resistant subline of the human ovarian cancer cell line IGROV-1.

The parental IGROV-1 human ovarian adenocarcinoma cell line was intermittently exposed to increasing concentrations of cisplatin to obtain resistant sublines. A stable resistant subline with a resistance factor of 8.4 had been developed after 9 months and 28 passages, which was denoted IGROV(CDDP). A high correlation coefficient of 0.97 was found between the log cell survival and the DNA-adduct peak level during the process of resistance development. IGROV(CDDP) was strongly cross-resistant to carboplatin and doxorubicin and moderately cross-resistant to etoposide, docetaxel, and topotecan. Only minor resistance against 5-fluorouracil was observed, whereas IGROV(CDDP) was not cross-resistant to methotrexate. Intracellular accumulation of cisplatin was 65% lower in IGROV(CDDP) as compared with parental IGROV-1 at 37 degrees C under normal conditions. Coincubation of cisplatin with the Na+/K+-ATPase inhibitor ouabain resulted in a more pronounced decrease in platinum accumulation in IGROV-1 (44% decrease) than in IGROV(CDDP) (26% decrease). Under energy-depleting conditions the accumulation of cisplatin in the parental cell line was approximately 60% lower than that observed under normal (energy [i.e., ATP] rich) culture conditions. In contrast, the accumulation in IGROV(CDDP) was not affected by ATP-depletion. There appeared to be no significant difference between the intracellular accumulation of platinum in the resistant and sensitive cells under conditions of energy deprivation or when the uptake was studied at 0 degrees C. In conclusion, abrogation of energy-dependent accumulation in IGROV(CDDP) seems to be a major mechanism of resistance to cisplatin in this cell line.

Adenocarcinoma↗
PubMed1998

Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro.

The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different administration schedules: (1) simultaneous incubation (C + T and C + S), (2) cisplatin followed by TPT or SN-38 (C --> T and C --> S), and (3) TPT or SN-38 followed by cisplatin (T --> C and S --> C). Median-effect analysis revealed synergistic cytotoxicity in seven of the eight cell lines used. In addition, a significant schedule-dependent synergistic cytotoxicity was found in three of the cell lines used, with C --> T (or C --> S) being the most active schedule. The formation and repair of total cisplatin-DNA adducts in the IGROV-1 ovarian cancer cell line and its cisplatin-resistant subline IGROV(CDDP) was not significantly affected by TPT on simultaneous incubation. In contrast, the number of cisplatin-DNA interstrand cross-links detected in the IGROV-1 and IGROV(CDDP) lines at certain time points was significantly lower after coincubation of the cells with TPT. Assessment of the cell-cycle distribution revealed an accumulation of cells in the G2/M phase after exposure to cisplatin. After exposure to TPT a different pattern was observed that was cell-type-specific and dependent upon the TPT concentration. Although up to 4-fold differences in topo I activity were observed in this panel of cell lines, these differences did not appear to be related to the synergy observed between cisplatin and TPT or SN-38. The observed synergy may at least partly be explained by the increased retention of cisplatin-DNA interstrand cross-links in the presence of topo I inhibitors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

The effect of dexamethasone on the uptake of cisplatin in 9L glioma and the area of brain around tumor.

The negative influence of dexamethasone (Dex) on the uptake of cisplatin in brain tumors was investigated in rats bearing 9L glioma. Dex or saline was given intraperitoneally prior to intravenous administration of cisplatin 5 mg/kg. Total Platinum (Pt) concentration was quantified with atomic absorption spectroscopy (AAS) in tumor, brain around tumor (BAT), normal brain and plasma. In the second experiment DNA-adducts of cisplatin were determined in tumor and BAT by AAS. In tumor, there was no difference in the Pt concentration and in the DNA-adduct level between the two treatment groups. In BAT, the Pt level in the Dex group was 0.20 microg/g (SD=0.10 microg/g), which was significantly lower than in the controls (0.53 microg/g (SD=0.21 microg/g); p < 0.001). In addition, the DNA-adduct level in BAT was 23% lower in the Dex treated rats (p=0.05). In normal brain the Pt concentration was 10-fold lower than in tumor tissue. Thus, Dex did not significantly limit the uptake of cisplatin in brain tumor nor did it influence the uptake in normal brain parenchyma. In contrast, in BAT that has a partially disrupted BBB, the concentrations of Pt and DNA-adduct formation were significantly decreased following pretreatment with Dex. The influence of Dex on limiting the effects of chemotherapy for brain tumors needs further study.

Animals↗
PubMed1998

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours.

Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.

Adult↗
PubMed1998

Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study.

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.

Adult↗
PubMed1997

Determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin in human plasma by sensitive high-performance liquid chromatography with fluorescence detection.

Two sensitive reversed-phase high-performance liquid chromatographic fluorescence methods, with simple sample handling at the site of the patient, are described for the determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin (9AC). For 9AC lactone, the sample preparation was a liquid-liquid extraction with acetonitrile-n-butyl chloride (1:4, v/v), whereas the sample preparation for 9AC total (lactone plus carboxylate) was a simple deproteinization with 5% perchloric acid-methanol (1:1, v/v), which results in the conversion of the carboxylate into the lactone form. The lower limits of quantitation were 50 pg/ml and 100 pg/ml for 9AC lactone and 9AC total, respectively. The within-run precisions at four tested concentrations were < or = 6.3% for 9AC lactone and < or = 5.3% for 9AC total. The between-run precisions were < or = 8.9% and < or = 5.6%, respectively. The assays were developed to enable pharmacological analysis of 9AC in a bioavailability and oral phase I study in patients with solid tumors.

Antineoplastic Agents↗
PubMed1997

Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats.

The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of correlation (> 0.8) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured.

Adenocarcinoma↗
PubMed1997

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor.

Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.

Administration, Oral↗
PubMed1997

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development.

Topoisomerase I inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase I inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase I inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase I inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and GI147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.

Animals↗
PubMed1997

Improved 32P-postlabelling assay for the quantification of the major platinum-DNA adducts.

For the improvement of chemotherapy with platinum (Pt)-containing drugs a sensitive assay to detect the induced Pt-DNA adducts is needed. Therefore, the 32P-postlabelling assay, described by Blommaert and Saris (Nucleic Acids Res., 1995, 23, 1300-1306), to detect the major adducts Pt-GG and Pt-AG has substantially been improved and compared with ELISA and AAS. For the quantification of the adducts, TpT was added as an internal standard immediately after isolation of the Pt-adducts from digested DNA samples. It was found that 32P-labelling of both GpG and ApG, the dinucleotides obtained after deplatination of the adducts, was equally efficient as that of TpT. To isolate the Pt-adducts on basis of a positive charge, the pH of DNA digests was adjusted to approximately 3 prior to separation by strong cation-exchange chromatography. For the subsequent deplatination a volume of only 12 microl of 0.2 M NaCN was used, which did not interfere with the following labelling step. The quantification of the 32P-labelled dinucleotides was performed by phosphorimaging of spots after separation on TLC as well as by 32P-counting of fractions collected after separation by HPLC. The method was used to determine adduct levels in in vitro cisplatin-treated DNA and in DNA isolated from cisplatin-treated cultured cells, tumor xenografts from cisplatin-treated mice, and from white blood cells and (tumor) tissues from cisplatin-treated patients. The results show a significant correlation with the adduct levels as determined with atomic absorption spectroscopy (high levels) or with specific antibodies (low levels). This assay appears to be useful for the determination of low levels of Pt-adducts in small DNA samples as present in clinical specimens such as blood and tumor tissue, but also in buccal mucosal cells and fine needle aspirates.

Animals↗
PubMed1997

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.

PURPOSE: This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS: Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS: Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION: The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.

Adult↗
PubMed1997

Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. RESULTS: Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function. CONCLUSION: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Administration, Oral↗
PubMed1996

Sensitive high-performance liquid chromatographic fluorescence assay for the quantitation of topotecan (SKF 104864-A) and its lactone ring-opened product (hydroxy acid) in human plasma and urine.

A sensitive reversed-phase high-performance liquid chromatographic fluorescence method is described for the simultaneous determination of topotecan (I) and the hydrolysed lactone ring-opened product hydroxy acid (II) in plasma and for the determination of I in urine. To 250 microliters of plasma, a 750-microliters volume of cold methanol was added to stabilize the pH-dependent conversion of I into II. In plasma, the lower limit of quantitation (LLQ) for both compounds was 0.10 ng/ml. The between-day variation for I at the LLQ was 7.1% and for II was 5.5%. Prior to injection, urine samples were acidified with orthophosphoric acid and diluted with phosphate-buffered saline (PBS). In urine, the calibration curve for I was linear in the range of 10 to 250 ng/ml and the LLQ was 10 ng/ml. The assay was developed to enable pharmacological analysis of I, in on-going phase I and II studies, in patients with solid tumors.

Camptothecin↗
PubMed1996

Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model.

The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (+/- 19 SD) ng/ml in plasma and 925 (+/- 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (+/- 6 SD) ng/ml and 289 (+/- 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.

Adenocarcinoma↗
PubMed1996

Docetaxel and paclitaxel inhibit DNA-adduct formation and intracellular accumulation of cisplatin in human leukocytes.

The purpose of this study was to determine the mechanism of the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin. Cisplatin-induced DNA-adducts and cisplatin accumulation were quantitated in peripheral blood leukocytes (WBC). The WBC were obtained from patients treated with docetaxel or paclitaxel in phase I/II studies and were incubated in vitro with cisplatin. In addition, blank whole-blood samples were obtained from patients and healthy subjects and incubated in intro with cisplatin or docetaxel/paclitaxel and cisplatin. The cisplatin-induced DNA-adduct levels measured in WBC after treatment with docetaxel or paclitaxel were significantly lower than those determined in non-pretreated WBC. Docetaxel and paclitaxel reduced the intracellular accumulation of cisplatin in WBC by 46-47%. If the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin also occurs in other normal tissues such as bone marrow, it may well contribute to the sequence dependent toxicity that has been observed in clinical studies.

Antineoplastic Agents↗
PubMed1996

Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.

Aged↗