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1.
K. Mross A. Hüttmann K. Herbst A.-R. Hanauske T. Schilling C. Manegold K. Burk D. K. Hossfeld 《Cancer chemotherapy and pharmacology》1996,38(3):217-224
NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety
of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical
studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity.
A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics
and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance
liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best
described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parantheses):
mean residence time (MRT) 16.5 (5.4– 42.3)h, terminal half-life 14.0 (8.2–30.5)h, volume of distribution at steady state (Vss) 11.4 (7.9–18.1) l/m2, and plasma clearance (Clp) 15.1 (3.6–36.4) ml min-1
m
-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 μg ml-1 h. The mean AUC (±SD) increased with the dose from 78.7±3.7 μg ml-1 h at 60 mg/m2 up to 202.8±157.2 μg ml-1 h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and
25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx. 99%. The percentage
reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUCfree. The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear
Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic
parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be
investigated in further studies.
Received: 8 May 1995/Accepted: 27 October 1995 相似文献
2.
F. Robert Shande Chen Antonius A. Miller Beverly C. Lee David C. Molthrop Richard H. Wheeler 《Cancer chemotherapy and pharmacology》1996,38(5):459-465
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 相似文献
3.
W. Kreis Daniel R. Budman Vincent Vinciguerra Kathleen Hock Joann Baer Richard Ingram Lee P. Schacter Scott Z. Fields 《Cancer chemotherapy and pharmacology》1996,38(4):378-384
Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation
settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients
with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m2 infused over 2 h on days 1 and 2, and G-CSF 5 μg/kg per day starting on day 3 until WBC was ≥10 000/μl. Qualitative, quantitative,
and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide
by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (Cpmax) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma
disposition demonstrated biphasic clearance, with mean T1/2α of 2.09±0.61 h, and T1/2β of 5.83±1.71 h. An AUC as high as 1768.50 μg.h/ml was observed at a dose of 1200 mg/m2. The total body clearance (TBC) showed an overall mean of 15.72±4.25 ml/min per m2, and mean volume of distribution (VDss) of 5.64±1.06 l/m2. The mean residual time (MRT) for etoposide was 6.24±1.61 h. In urine, etoposide but not etoposide phosphate, was identified
with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide
phosphate is converted into etoposide with the linear dose-related Cpmax and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic
parameters of high- dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values
for the clinically important Cpmax and AUCs, clearance, terminal T1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may
offer the advantage of ease of administration.
Received: 18 July 1995/Accepted: 20 October 1995 相似文献
4.
M. Venturini L. Del Mastro Franco Testore Marco Danova Ornella Garrone Claudio Lanfranco Fabio Latini Mario R. Sertoli Rita Lionetto Paola Queirolo Andrea Ardizzoni Riccardo Rosso 《Cancer chemotherapy and pharmacology》1996,38(6):487-494
To verify whether the association of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) would
allow both the acceleration and the dose escalation of the cyclophosphamide/epidoxorubicin/5-fluorouracil (CEF) regimen as
first-line therapy in advanced breast cancer patients, we conducted a dose-finding study. Cohorts of three consecutive patients
received cyclophosphamide (Ctx, dose range 800 –1400 mg/m2), epidoxorubicin (Epidx, dose range 70–100 mg/m2), and 5-fluorouracil (5-Fu, 600 mg/m2, fixed dose) given as an intravenous bolus on day 1 every 14 days; GM-CSF at 5 μg/kg given as a subcutaneous injection from
day 4 to day 11; and EPO at 150 IU/kg given as a subcutaneous injection three times a week. In no single patient was any dose
escalation allowed. A total of 14 patients entered the study. At the 4th dose level (Ctx 1400 mg/m2, Epidx 100 mg/m2, 5-Fu 600 mg/m2), two patients had dose-limiting mucositis and one patient developed dose-limiting neutropenia. Therefore, the 3rd cohort
received the maximum tolerated dose, i.e. Ctx at 1200 mg/m2, Epidx at 90 mg/m2, and 5-Fu at 600 mg/m2, given every 18.5 (±2.5) days. Toxicity was moderate and manageable in an outpatient setting. Only 1 admission at the 4th
dose level was required. Throughout the 4 dose levels there was no toxicity-related death; grade IV leukopenia ranged from
24% to 75% of cycles and grade IV thrombocytopenia ranged from 6% to 8%. No grade IV anemia was recorded. Increasing the doses
of Ctx and Epidx while maintaining a fixed dose of 5-Fu with the support of both EPO and GM-CSF allows safe acceleration and
dose escalation of CEF chemotherapy. Further controlled studies will evaluate the activity and efficacy of this strategy.
Received: 8 October 1995/Accepted: 1 March 1996 相似文献
5.
G. S. Price Rodney L. Page J. Edmond Riviere J. Mark Cline D. E. Thrall 《Cancer chemotherapy and pharmacology》1996,38(2):129-135
Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m2 orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m2. Physical or laboratory signs of toxicity were not observed in dogs receiving oral lonidamine, but severe vomiting and signs
of acute hepatic and pancreatic toxicity were observed in dogs receiving intravenous doses that exceeded 400 mg/m2. The area under the lonidamine concentration versus time curve (AUC) in dogs receiving 200, 400, and 800 mg/m2 of lonidamine intravenously was a 1.8-, 3.3-, and 8.7-fold higher than in dogs receiving oral lonidamine. This suggests that
the bioavailability of oral lonidamine may be limited. However, centrilobular hepatocellular swelling and vacuolation were
observed in dogs receiving oral lonidamine. Serum alanine aminotransferase (ALT) activity was increased in dogs receiving
intra-venous lonidamine. These findings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in
only 1/4 dogs receiving 400 mg/m2 of lonidamine intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy.
Therefore, this dose and route appears to be a viable and controllable method for prospective quantification of lonidamine
interaction with systemic chemotherapy and/or hyperthermia.
Received: 8 October 1993 /Accepted: 9 October 1995 相似文献
6.
Margaret E. Tonda Richard L. Heideman William P. Petros Henry S. Friedman Daryl J. Murry J. H. Rodman 《Cancer chemotherapy and pharmacology》1996,38(5):395-400
Purpose: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children
given in combination with cyclophosphamide and etoposide. Patients and methods: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of
age with newly diagnosed, malignant central nervous system tumors. Patients received cyclophosphamide, 1.2 g/m2, on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m2, each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC)
of 5, 6.5 or 8 mg/ml . min based on each patient’s measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic
parameters were determined after course 1 and then after every third course of therapy. Results: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m2, respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin
clearance for four children less than 1 year of age was 76 (66–84) ml/min per m2, significantly lower (P=0.05) than the value of 131 (80–158) ml/min per m2 for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course
1 to course 4 of therapy. The decrease was greater than 20% (range 20–53%) in 7 of the 12 patients studied. Conclusion: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported
for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance
per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR
that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable
for patients treated at a TAUC of 6.5 mg/ml . min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin
dose required for this AUC was 767 mg/m2.
Received: 13 July 1995/Accepted: 18 December 1995 相似文献
7.
K. Mori Tsukasa Ohnishi Kohki Yokoyama Keigo Tominaga 《Cancer chemotherapy and pharmacology》1997,39(4):327-332
A phase I study was performed to establish the optimum dose for combination therapy with infusional cisplatin and irinotecan
(CPT-11) in non-small-cell lung cancer (NSCLC). The subjects were 20 patients with a performance score of 0–2 with untreated
advanced NSCLC. Cisplatin was administered by 5-day continuous intravenous infusion at 20–25 mg/m2 per day. CPT-11 was administered by bolus infusion at a starting dose of 20 mg/m2 on days 1 and 8 or 60 mg/m2 per day on day 1 alone, followed by serial increments of 20 mg/m2. Since grade 4 granulocytopenia was observed in two of the five patients receiving 20 mg/m2 per day cisplatin (days 1–5) and 100 mg/m2 CPT-11 (day 1), and since one of them developed severe pneumonia and sepsis associated with the granulocytopenia, the regimen
was considered to be intolerable. In the same patient, grade 4 thrombocytopenia and grade 3 diarrhea were observed. Therefore,
the optimum dose appeared to be 20 mg/m2 per day (days 1–5) for cisplatin and 80 mg/m2 (day 1) for CPT-11. The side effects were grade 2 diarrhea in one of three patients, and grade 2 vomiting in three patients,
but grade ≥2 hemotoxicity was not observed. This combined regimen resulted in a partial response in 9 out of 19 assessable
patients. The dose-limiting factor in this combination therapy was granulocytopenia, and a high efficacy rate was obtained.
Received: 14 August 1995 / Accepted: 3 June 1996 相似文献
8.
Etienne Chatelut Christine Chevreau Valérie Brunner Mathilde Martinez Georges Houin Roland Bugat Pierre Canal 《Cancer chemotherapy and pharmacology》1995,35(5):391-396
Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study
of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable
carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage
of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method
allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired
renal function. The recommended AUC for phase II study is 4 mg ml-1 min.
Received: 9 May 1994/Accepted: 16 August 1994 相似文献
9.
S. P. Khor H. Amyx Stephen T. Davis Donald Nelson David P. Baccanari Thomas Spector 《Cancer chemotherapy and pharmacology》1996,39(3):233-238
The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihy-dropyrimidine dehydrogenase
(DPD) inactivator, 5-ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination
with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. Method: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed
by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to
the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical
toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. Results: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL=0.47B0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution
(Vc) increased proportionately with body weight (Vc=0.58 B0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to
the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h)
or (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85
was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based
on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v.
bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m2 of 5-FU, respectively. Discussion: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose
of 5-FU is needed in patients treated with 776C85.
Received: 6 October 1995/Accepted: 28 May 1996 相似文献
10.
J. F. Cleary Rhoda Arzoomanian Donna Alberti Chris Feierabend Barry Storer Pauline Witt P. P. Carbone George Wilding 《Cancer chemotherapy and pharmacology》1997,39(4):300-306
Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole
has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole
may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose
for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU
(375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from
30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles.
All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia
and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses
were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as
evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate
dose for further phase 11 studies.
Received: 20 October 1995 / Accepted: 16 June 1996 相似文献
11.
N. J. Meropol Yousef M. Rustum Nicholas J. Petrelli Miguel Rodriguez-Bigas Cheryl Frank Dah H. Ho Marilyn Kurowski Patrick J. Creaven 《Cancer chemotherapy and pharmacology》1996,37(6):581-586
A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer.
Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts
were treated at 200, 250, 300, and 350 mg/m2 of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each
28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at
350 mg/m2 UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously
untreated patients, UFT at 350 mg/m2 was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously
untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m2) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide
interpatient variations. Plasma levels of 5-FU (Cmax 1.4±1.9 μM) were comparable to those achieved with protracted venous infusions, and folate levels (Cmax 6.1±3.6 μM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will
compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs.
Received: 20 January 1995/Accepted: 29 June 1995 相似文献
12.
Naomi Nagai Masafumi Kinoshita H. Ogata Daijiro Tsujino Yuji Wada Kazuhiko Someya Tetsuro Ohno Keisou Masuhara Yoshio Tanaka Katsuhiko Kato Haruki Nagai Akira Yokoyama Yuzou Kurita 《Cancer chemotherapy and pharmacology》1996,39(1-2):131-137
Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity
after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor).
Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method.
Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea
nitrogen (BUN), serum creatinine (SCr), plasma and urinary β2-microglobulin (BMGp and BMGu), urinary N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dtmax), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from
time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity
markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic
studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 μg/ml in a standard continuous infusion
schedule over 2 h and 4 h.
Received: 2 May 1995/Accepted: 25 March 1996 相似文献
13.
Purpose: The major pharmacokinetic parameters of unchanged cisplatin (CDDP) related to nephrotoxicity were evaluated in rats in vivo
using a pharmacodynamic model. Methods: CDDP was administered according to various dosing schedules (single bolus, intermittent bolus, or continuous infusion).
Unchanged CDDP in plasma and urine was quantified using high-performance liquid chromatography (HPLC). The pharmacokinetics
were assessed by model-independent methods. The relationship between pharmacokinetics and BUN levels was evaluated using a
sigmoid maximum response (Emax) model. Results: Unchanged CDDP showed linear pharmacokinetics after single bolus injections of 1 to 5 mg/kg CDDP. Nephrotoxicity was ameliorated
following intermittent bolus injection (1 mg/kg per day for 5 days) and continuous infusions (over 2 and 3 h) of the same
CDDP doses (5 mg/kg), although these dosing schedules did not change the area under the concentration-time curve (AUC), total
clearance (Clt), urinary excretion of unchanged CDDP or kidney platinum levels significantly. The maximum BUN level, as a
nephrotoxicity marker, showed dose-related increases after single bolus injection of 1 to 5 mg/kg CDDP and after 3-h infusion
of 5 to 25 mg/kg. The pharmacodynamic relationship between the maximum BUN level and Cmax and between the maximum BUN level and AUC were apparently different between single bolus injection and 3-h infusion. The
maximum BUN level was related to the AUC calculated by plasma concentrations of unchanged CDDP greater than the threshold
level (AUC>Cmin), a relationship most successfully described by the signoid Emax model, regardless of CDDP dose and schedule. The plasma threshold level of unchanged CDDP was determined as 0.9 μgPt/ml in
rats. Conclusions: The present results substantiated the importance of C×T (AUC) value as an indicator of CDDP-induced nephrotoxicity in vivo
as well as of tumor cell-killing effect of CDDP in vitro. The AUC>Cmin of unchanged CDDP was found to be an important pharmacokinetic parameter predicting CDDP nephrotoxicity.
Received: 12 February 1996 / Accepted: 5 September 1996 相似文献
14.
Federico Innocenti Romano Danesi Antonello Di Paolo Barbara Loru Claudio Favre Margherita Nardi Guido Bocci Denise Nardini Pierantonio Macchia Mario Del Tacca 《Cancer chemotherapy and pharmacology》1996,37(5):409-414
Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated
in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL)
in remission received daily doses of 6-MP given at 25 mg/m2 and i.v. infusion of high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml-1. Concurrent treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108% and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2 produced mean increases of 110% and 230% in the Cmax and AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular
concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 μg/ml of MTX. The
present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in
the plasma Cmax and AUC of 6-MP in humans and animals.
Received: 13 December 1994/Accepted: 12 July 1995 相似文献
15.
J. Liliemark Freidoun Albertioni Gunnar Juliusson Staffan Eksborg 《Cancer chemotherapy and pharmacology》1996,38(6):536-540
Cladribine is a newly developed antimetabolite with promising activity in lymphoproliferative disorders. Recent pharmacokinetics
investigations have suggested that there is a relationship between its plasma area under the concentration versus time curve
(AUC) and the degree of neutropenia posttreatment as well as the therapeutic outcome in hairy-cell leukemia. To enable a simple
estimation of the plasma AUC, a limited sampling strategy was developed. Stepwise linear regression was used to determine
which were the most important data points for estimation of the plasma AUC after 2-h i.v. infusion, s.c. injection (5 mg/m2), and oral administration (10 mg/m2) in 27 patients. The most important data points after i.v. infusion in 12 patients were 1, 4, and 24 h, in order of importance.
The AUC could be estimated as 2.9081×C
1h
+5.1851×C
4h
+20.3265×C
24h
.The accuracy and precision (mean value±SD for the determined/estimated AUC was 0.99±0.053) of the model could not be increased
by the addition of more data points. A somewhat lower accuracy and precision (0.96± 0.089) was seen with the 2-, 4-, and 24-h
data points. These were used to test the regression technique prospectively for the estimation of the AUC after i.v. administration
in another set of 10 patients. The accuracy and precision of the estimation of the AUC was similar in this group (1.01±0.109).
In all, 11 patients were treated orally (10 mg/m2) and 10 patients were treated by s.c. injection (5 mg/m2). The most important data points for estimation of the AUC were 2.5, 24, and 0.5 h after oral administration (AUC=0.8630×C
0.5
h+ 4.2337×C
2.5h
+45.4364×C
24h
) and 9, 1, and 16 h after s.c. injection (AUC=1.8821×C
1h
+16.4256×C
9h
+ 25.4518×C
16h
). The accuracy and precision were 1.01±0.064 after oral dosing and 0.99±0.11 after s.c. injection. The derived mathematical
models are reliable for estimation of the plasma AUC of cladribine after 2-h i.v. infusion, oral administration, and s.c.
injection.
Received: 8 October 1995/Accepted: 1 March 1996 相似文献
16.
L. J. C. van Warmerdam Geert-Jan Creemers S. Rodenhuis Hilde Rosing Maureen de Boer-Dennert Jan H. M. Schellens W. W. ten Bokkel Huinink Brian E. Davies Robert A. A. Maes Jaap Verweij Jos H. Beijnen 《Cancer chemotherapy and pharmacology》1996,38(3):254-260
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 (AUCclosed) was 8.74 (range 2.3–16.3) μM min per day, and the mean AUC of the ring-opened form (AUCopen) was 11.5 (range 3.2–46.0) μM 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 AUCclosed and that of 12.6%, for the AUCopen. 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.
Received: 15 June 1995/Accepted: 19 October 1995 相似文献
17.
L. K. Webster Martha E. Linsenmeyer Danny Rischin Maureen E. Urch David M. Woodcock Michael J. Millward 《Cancer chemotherapy and pharmacology》1997,39(6):557-560
Docetaxel (Taxotere, Rhone-Poulenc Rorer) and etoposide are water-insoluble drugs formulated with polysorbate 80 for intravenous
administration. We have previously reported that surfactants, including polysorbate 80 and Cremophor EL, can reverse the multidrug
resistance (MDR) phenotype in an experimental system and that plasma Cremophor EL concentrations measured following a 3-h
infusion of paclitaxel were ≥1 μl/ml, sufficient to modulate MDR in vitro. The purpose of this study was to measure polysorbate
80 plasma concentrations in patients following intravenous administration of etoposide or docetaxel using a bioassay in which
MDR-expressing cells are incubated with daunorubicin (DNR) plus 50/50 growth medium/plasma and equilibrium intracellular DNR
fluorescence is measured by flow cytometry. In vitro experiments show maximal reversal of MDR at concentrations of 1.0–2.0 μl/ml
and 50% reversal at 0.2–0.3 μl/ml. Patients received docetaxel at 75 mg/m2 (five patients) or 100 mg/m2 (four patients) (total dose 125–178 mg, containing 3.12–4.45 ml polysorbate 80) over 60 min. The median end-infusion polysorbate
80 concentration was 0.1 μl/ml (range 0.07–0.41 μl/ml). Only one patient had a level of >0.2 μl/ml. Five patients received
intravenous etoposide at 120 mg/m2 over 45–120 min (total dose 180–250 mg, containing 0.67–0.93 ml polysorbate 80). In the end-infusion plasma sample, polysorbate
80 was not detectable (<0.06 μl/ml) in any patient. Plasma polysorbate 80 levels following an intravenous infusion of 120 mg/m2 etoposide or of docetaxel at doses used in Phase II trials, are insufficient to show modulation of MDR in vitro.
Received: 21 July 1996 / Accepted: 4 November 1996 相似文献
18.
J. R. W. Masters Barbara J McDermott Stephen Harland Michael C. Bibby Paul M. Loadman 《Cancer chemotherapy and pharmacology》1996,38(1):59-64
ThioTEPA is given intravesically in a variety of schedules to treat superficial bladder cancer. In this study, the influence
of the dose of ThioTEPA and the volume of instillate on the dose rate to the tumour and the systemic uptake of ThioTEPA was
investigated in eight patients with pTa or pTl disease. Each patient received four courses of ThioTEPA consisting of 30 mg
of drug/30 ml of distilled water, 30 mg/60 ml, 60 mg/30 ml and 60 mg/60 ml. Blood and urine samples were obtained for 8 h
following instillation, and ThioTEPA and TEPA levels were measured. The AUC∞ values (areas under the concentration-time curve, extrapolated to infinity) in plasma were approximately 2 factors higher
at the two 60-mg doses. However, the AUC value in the bladder was nearly 70% higher when 60 mg of drug was instilled in 30 ml
of distilled water as compared with 60 mg in 60 ml. Thus, by decreasing the volume of instillate it is possible to increase
the dose rate to the tumour without increasing the systemic toxicity.
Received: 27 March 1995/Accepted: 4 August 1995 相似文献
19.
O. Pagani M. Zucchetti C. Sessa J. de Jong M. D’Incalci M. De Fusco A. Kaeser-Fröhlich A. Hanauske F. Cavalli 《Cancer chemotherapy and pharmacology》1996,38(6):541-547
NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and
better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after
both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611.
Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive
oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m2 on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m2 was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m2. NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC)
methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least
the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the
plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially
in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m2 after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume
of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to
the dose. The urinary excretion of NK611 corresponded to 10–15% of the dose after administration by both routes, whereas that
of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide
involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m2 for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated
or have undergone previous chemotherapy only once.
Received: 26 November 1995: Accepted: 27 March 1996 相似文献
20.
A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve 总被引:2,自引:0,他引:2
Saad Ghazal-Aswad A. Hilary Calvert David R. Newell 《Cancer chemotherapy and pharmacology》1996,37(5):429-434
The aim of this study was to develop and validate a simple and rapid method for the estimation of the area under the free
carboplatin plasma concentration versus time curve (AUC). The relationship between the carboplatin AUC and the total plasma
platinum (Pt) concentration 24 h after treatment was studied using data from 49 patients treated with 20–1600 mg/m2 carboplatin as a 60–100 min infusion (median 60 min). The relationship was confirmed by the in vitro incubation of carboplatin
in human plasma and prospectively validated in 13 ovarian cancer patients. Free carboplatin was separated by ultrafiltration
(MW cut off 30,000), and free and total Pt measured by atomic absorption spectrophotometry. There was a linear relationship
in vivo between the 24 h (median 24.4; range 16.3–27.3 h) total plasma Pt concentration (μM) and free carboplatin AUC (mg/ml.min): AUC=(24 h Pt+0.3)/0.82 (r
2=0.93, AUC median 5.8 (0.13–28)mg/ml.min, 24 h Pt median 4.4 (0.1–23) μM). A similar relationship was observed in vitro [AUC=(24 h Pt +0.1)/0.93 (r
2=0.98, AUC median 7.9 (2.0–17) mg/ml.min, 24 h Pt median 7.1 (1.8–15) μM)]. The relationship derived from the in vivo data gave an unbiased and reasonably accurate estimate of the measured carboplatin
AUC in 13 patients (AUC=5.1–8.7 mg/ml.min, GFR=59–129 ml/min, infusion time 30–45 min, 24 h sampling time 22.9–24.5 h), giving
a percentage mean error of −4.2% and root mean squared percentage error of 11.5%. These results show that the analysis of
a single blood sample taken 24 h after carboplatin administration can be used to produce an unbiased and reasonably accurate
measure of the free carboplatin AUC. Unlike published limited sampling strategies, this method is not complicated by the need
to accurately control the duration of the carboplatin infusion or the time at which the sample is taken.
Received: 13 January 1995/Accepted: 14 May 1995 相似文献