Ceftibuten Pharmacokinetics and Pharmacodynamics

Kearns, Gregory L.; Young, Ronald A.

doi:10.2165/00003088-199426030-00002

Cited by 33 publications

(29 citation statements)

References 48 publications

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“…In vitro synergism has been demonstrated between paclitaxel and hydroperoxyifosfamide, an activated ifosfamide metabolite, against cisplatinsensitive and -resistant Ovarian Carcinoma cell lines when paclitaxel preceded hydroperoxy-ifosfamide or during concurrent exposure (Liebmann et al, 1994;Klaassen et al, 1996). Based on these preclinical in vitro experimental data, we believe that the sequence and infusion times regarding docetaxel and ifosfamide, as applied in the present study, might lead to potential in vivo synergism between these two drugs (Kearns et al, 1995). Moreover, our prior experience with paclitaxel -ifosfamidecisplatin (Kosmas et al, 2000a, b;2001) or docetaxel -ifosfamide -cisplatin (Kosmas et al, 2002) combinations has demonstrated their feasibility in phase I and phase II studies in advanced solid tumours and lung cancer in particular.…”

Section: Discussionmentioning

confidence: 58%

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Kosmas

Tsavaris²,

Malamos

et al. 2003

Br J Cancer

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Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I -II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel -ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70 -100 mg m À2 over 1 h on day 1 followed by ifosfamide 5 -6 g m À2 divided over days 1 and 2 (2.5 -3.0 g m À2 day À1 over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32 -72) years and performance status (WHO) of 1 (range, 0 -2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3 -68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3 -24 months), median time to progression 6.5 month (0.1 -26 month), and median overall survival 13 months (0.1 -33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients -with 63% developing grade 4 neutropenia (p7 days) and in 12% of these FN, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 12%, grade 1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle. In conclusion, the present phase I -II study determined the feasibility of the docetaxel -ifosfamide combination, defined the MTD and demonstrated the encouraging activity of the regimen in phase II, thus warranting further randomised phase III comparisons to singleagent docetaxel or combinations of the latter with other active agents. ) has demonstrated a broad spectrum of activity against a variety of advanced solid tumours, and breast cancer represents the first in which docetaxel has been successfully tested (Salminen et al, 1999). In particular, for patients with prior anthracycline-based therapy, taxanes represent the treatment of choice in the salvage setting, since previously applied agents have demonstrated infe...

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Section: Discussionmentioning

confidence: 58%

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Kosmas

Tsavaris²,

Malamos

et al. 2003

Br J Cancer

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“…This study has demonstrated the feasibility of two oral schedules of Ro 31-7453 with an acceptable safety profile. In addition, the current available pharmacokinetic data compare favorably with the nonlinear kinetics of Vinca alkaloids (14,15) and paclitaxel (16). The 14-day schedule of oral Ro 31-7453 at the recommended dose of 125 mg/m 2 bid is being evaluated in Phase II trials in patients with breast, lung, and colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

Salazar

Bissett

Twelves

et al. 2004

Clinical Cancer Research

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Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models.Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively.Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40 -77 years), and median Karnofsky performance status was 80 (range, 60 -100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m 2 twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m 2 bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m 2 bid and 125 mg/m 2 bid for the 7-and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t 1/2 of ϳ9 h and a t max of ϳ4 h. One patient with pretreated lung cancer had a partial response. Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m 2 bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.

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“…A nonlinear pharmacokinetic model with Michaelis-Menten kinetics at distribution and elimination processes was suggested for paclitaxel. 7,17) However, we used the linear model because the difference in the AUC between the nonlinear and the linear models was minimal and because the linear model is easier than the nonlinear model to handle in pharmacodynamic analysis. 15) Pharmacodynamic study The entire time course of leukopenia after treatment with paclitaxel was fitted in each patient by using a pharmacodynamic model which we have recently developed.…”

Section: Patientsmentioning

confidence: 99%

Pharmacodynamic Modeling of the Entire Time Course of Leukopenia after a 3‐Hour Infusion of Paclitaxel

Minami

Sasaki

Watanabe

et al. 2001

Japanese Journal of Cancer Research

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The entire time course of leukopenia after anticancer treatment is clinically more relevant than a singly measured nadir count. In order to identify factors associated with neutropenic fever, a mechanistic pharmacodynamic model with two compartments corresponding to leukocytes in bone marrow and peripheral blood was applied to describe the time course of leukopenia. Key words: Pharmacokinetics -Pharmacodynamics -Leukopenia -Fever -ChemotherapyLeukopenia is the primary toxicity of many anticancer agents and precludes dose escalation or scheduled administration of repeated cycles. Most pharmacodynamic analyses of anticancer agents focus on this toxicity, and a singly measured nadir leukocyte count or the surviving fraction of leukocytes at the nadir (nadir count divided by the pretreatment count) is modeled.1-4) However, leukopenia changes continuously with time after treatment, and the singly measured nadir count is not the best predictor of clinically relevant events, including fever or toxic death, considering that patients with prolonged leukopenia have a greater risk of infection than patients with more rapid recovery.5) The time period during which the leukocyte count remains below a certain level (i.e., 1000 or 2000/µl, Fig. 1a) or the area between the curve of time versus leukocyte counts and the line of a specific leukocyte count (Fig. 1b) may be clinically more important than the singly measured nadir count (Fig. 1c). Not only the magnitude of leukopenia, but also the time course of leukopenia should be considered in pharmacodynamic analysis of anticancer agents.In most of the conventional pharmacodynamic analyses, information on plasma concentrations of the drug, which change with time, is summarized by a time-independent parameter such as the area under the time-concentration curve (AUC), the peak concentration, or the time above a threshold concentration. 2,[6][7][8][9][10] The relationship between one of these summary parameters (e.g., AUC) and the nadir count, which is also a summary parameter of pharmacodynamics, is evaluated by using a model. In this case, patients with the same AUC but a different time course of plasma concentrations would have the same nadir value, although they have a different time course of leukopenia. It is useful to consider the time course of the drug concentration when the time course of leukopenia after treatment with an anticancer drug is modeled. Although pharmacodynamic models for the time course of leukopenia have been reported, they were mathematical and ignored the time course of the drug concentration. 11-14)Recently we developed a model to describe the entire time course of leukopenia after treatment with anticancer agents by using the time course of plasma concentrations as input into the model. 15) By using the model, the time that leukocyte counts remain below a certain value or the area between the time course of leukopenia and the line of a specific leukocyte count can be estimated. In this study, we have applied the pharmacodynamic model to the time course ...

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Ceftibuten Pharmacokinetics and Pharmacodynamics

Cited by 33 publications

References 48 publications

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

Pharmacodynamic Modeling of the Entire Time Course of Leukopenia after a 3‐Hour Infusion of Paclitaxel

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