Phase I clinical and pharmacological study of 72-hour continuous infusion of etoposide in patients with advanced cancer (original) (raw)
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Pharmacokinetics of VP16-213 given by different administration methods
Cancer Chemotherapy and Pharmacology, 1982
Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T1/2 ß), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m2, and 15.7±1.8 l/m2; in children 3.37±0.5 h, 39.34±6.6 ml/min/m2, and 9.97±3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was
Pharmacotherapy, 1999
To determine whether therapeutic drug monitoring can enhance administration of etoposide in patients with drug-responsive neoplasms. Prospective, open-label study. University-affiliated hospital and cancer center. Sixteen patients with small cell lung cancer or low-grade non-Hodgkin's lymphoma. Patients were treated with etoposide, 25 mg/m2/day over 24 hours by continuous infusion for 35 days. Peripheral blood samples were collected twice a week to measure etoposide levels. Plasma was separated, frozen and stored at -20 degrees C until assayed. Steady-state plasma etoposide concentrations (ECpss) were determined and used to calculate total systemic clearance (Clsys). Despite differences in dosage and administration schedules, etoposide Clsys was similar to previous reports. In addition, a biexponential relationship between ECpss and absolute neutrophil count was demonstrated by nonlinear least squares estimation. Values generated from this equation indicated that ECpss above 1.5 microg/ml was strongly associated with grade III-IV leukocyte toxicity. Although less precise, there may also be a correlation between ECpss and antitumor activity. Based on these findings, we propose a pharmacodynamic construct that uses measurements of both pharmacokinetic (ECpss, Clsys) and pharmacodynamic (hematologic toxicity, tumor response) parameters for patients with etoposide-sensitive tumors. Therapeutic drug monitoring may be able to mitigate hematologic toxicity.
Cancer Chemotherapy and Pharmacology, 1992
The objectives of this study were to define the pharmacodynamics of etoposide and to develop potentially useful models (1) to estimate the plasma clearance using a limited number of samples and (2) to describe the relationship between clearance and the dose-limiting toxicity. A total of 17 patients with extensive-stage small-cell lung cancer were treated with 150 mg/m2 etoposide daily for 3 consecutive days and with 100 rag/m2 cisplatin on day 3 only. Both drugs were given intravenously over 1 h. Treatment was repeated every 21 days for up to six courses. All patients were newly diagnosed (no previous chemotherapy or irradiation) and had a performance status of 0-2. Six patients achieved a complete response as confirmed by repeat bronchoscopy and five patients showed a partial response, for an overall objective response rate of 65% (95% confidence interval, 38%-87%). The median survival was 8 months (range, 1-24+ months). The dose-limiting toxicity was neutropenia. Etoposide pharmacokinetics were measured during the first course and determinations were repeated during courses 3 or 4 and 6. Complete blood counts were obtained weekly. Correlations for etoposide clearance and hematologic toxicities were evaluated for 17 initial courses and for an overall number of 33 courses. Pharmacodynamic correlations were significant for graded hematologic toxicities, as well as nadirs of leukocytes, neutrophils, and platelets for the initial courses and for all courses. To reduce the requirement for numerous blood samples, a limited sampling model was developed to estimate the area under the concentration versus time curve (AUC) with the following equation: AUC = 15.45+3.86 x C2+7.10 • C4, where C2 and C4 represent the etoposide concentrations at 2 and 4 h, respectively. The total plasma clearance was calculated as the dose divided by the AUC; correlations with toxicity were better for clearance expressed in milliliters per minute than for that expressed in milliliters per minute per square meter of body surface area. The absolute neutrophil count at the nadir (ANCn) can be estimated by the following pharmacodynamic model, which is based on 33 courses: ANCn =~3.399+0.024 XEcl,
Cancer Chemotherapy and Pharmacology, 2013
Purpose PM00104 (Zalypsis Ò) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk). Methods Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 ? 3 patients per cohort). Plasma samples were collected for PK analysis. Results DLTs comprised severe neutropenia lasting [5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay[2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m 2. Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease C3 months. Conclusions PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed.
Pharmacokinetic Study of High Dose Etoposide Infusion in Patients with Small Cell Lung Cancer
Acta Oncologica, 1988
The plasma pharmacokinetics of etoposide administered at a dose of 600 mg/m*/day over 3 consecutive days to 19 patients are described. High performance liquid chromatography with ultraviolet detection was used to determine the etoposide levels. The plasma concentration time curve showed a biphasic decay. When given as a 6-h infusion of 600 mg/m2 on each of 3 consecutive days, the peak plasma levels (PPL) were 45.6 k SD 10.5 pg/ml, and the area under the curve (AUC) values were 1379.6kSD 332.4 pg/rnl/h. In 2 patients a second cycle 28 days later as a 72-h infusion at a total dose of 1800 mg/m2 was given, and in these cases the mean PPL was 30 p g h l compared to 63 &ml for the 6h infusion in the same patients, and the mean AUC was 1239 pg/ml/h compared to 1952.5 pg/ml/h. There was no correlation with age, sex, the duration of or the severity of the neutropenia. It is concluded that high dose etoposide has higher PPL and improved concentration x time values when given as 3 consecutive daily infusions 18 h apart than as a continuous 72 h infusion.
Cancer Research, 1989
We optimized the modulation of drug resistance by the irreversible augmentation of cytotoxicity of coincubating vinblastine (VNB) with VP-16 and the reversible increase in cytotoxicity of coincubation of verapamil (VPL) with VNB and VP-16. VPL was administered as a loading dose (i.v.) (0.15 mg/kg) and then administered as a constant infusion (0.005 mg/kg) over 6 days. 24 h after verapamil, VNB 2 mg/m2 IVP was administered and followed l h later by a 5-day simultaneous continuous infusion of VP-16 (200 mg/m2/day) to seven pediatrie patients (11 courses) with refractory malignancies. The mean age at treatment was 7.5 ±5.3 years, mean prior anthracycline dose (303 ±210 me/in') with a range of 0-606 mg/m2. Toxicity was limited to cardiac and hematological. The median nadir of the VVBCwas 900 at 14.5 ±0.5 days and platelet count 32,000 at 15.5 ±0.8 days. There were two episodes of bacterial sepsis both of which responded to i.v. antibiotics. Five of 11 courses resulted in first-degree block and one course in second-degree block. At Hour 120 of the VPL infusion the PR interval was 0.18 ± 0.01 versus 0.13 ±0.01 at Hour O(P < 0.0004). The ejection fraction by twodimensional echocardiogram was not significantly different at Hour 0, 24, or 120 of the infusion (60.6 ±2.7 versus 52.7 ±5.1 versus 51.8 ± 5.0%). The cardiac index was also not significantly different at Hour 0, 24, or 120 (4.39 ±0.2 versus 4.21 ± 0.6 versus 3.91 ± 0.5 liters/min/m2). The 15-min VPL level was 1954.5 ±391/ng/ml and steady state levels at Hour 24 and 120 of the infusion were 468.1 ±59 and 422.8 ±52 ng/ ml, respectively. Two of 11 treatment courses resulted in hypotension secondary to inordinately high 24-h levels of VPL (1233 and 1263 ng/ ml). These two episodes required inotropic support but did not require the discontinuation of VPL. There were 8 of 11 partial responses, the majority of which consisted of peripheral cytoreduction of leukemic blasts and one M-2A response in AML. The levels of VPL achieved in this study have been shown to augment the in vitro cytotoxicity of vinblastine and VP-16 to resistant cell lines. Further clinical studies are needed to determine the maximal-tolerated dose of VPL in a Phase I study and to examine its efficacy in selected relapsed pediatrie patients.
Pharmacokinetics of teniposide (VM26) and etoposide (VP16-213) in children with cancer
Cancer Chemotherapy and Pharmacology, 1982
The clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography-electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VDc), steady-state volumes of distribution (VDss) and systemic clearances (Cls) of VM26 and VP16-213; with the VDo VD~s, and Cls all being smaller for VM26. Systemic clearances determined by model-independent methods were 5.2 + 1.0 ml/min/me(mean +_ SD) for VM26 and 17.8 + 11.2 ml/min/m 2 for VP16-213. The major metabolites detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.
Annals of Oncology, 2006
Background: Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy.