共查询到20条相似文献,搜索用时 31 毫秒
1.
Ouellet D Periclou AP Johnson RD Woodworth JR Lalonde RL 《Cancer chemotherapy and pharmacology》2000,46(3):227-234
Purpose: To evaluate the population pharmacokinetics of pemetrexed disodium in cancer patients enrolled in four different open-label,
multicenter, nonrandomized phase II studies. Methods: Pemetrexed disodium was administered as a 10-min intravenous infusion (600 mg/m2) every 21 days. A total of four blood samples were to be collected each cycle per patient (n=103 patients) during cycles 1 and 3. Plasma concentration-time data were analyzed by nonlinear mixed-effect modeling using
NONMEM to estimate pemetrexed disodium pharmacokinetic parameters (mean, and between- and within-patient variability) as well
as relationships between the pharmacokinetic parameters and various patient-specific factors (demographic and physiologic
data). Results/Conclusions: The pharmacokinetics of pemetrexed disodium were best characterized by a two-compartment model with initial distribution
and terminal elimination half-lives of 0.63 h and 2.73 h, respectively. The typical value of systemic clearance (CL) in liters
per hour included a relationship to creatinine clearance (CrCL) with a slope of 0.0292. Typical values of central volume (Vc), distributional CL (Q), and peripheral volume (Vp) were 11.3 l, 3.21 l/h, and 5.20 l, respectively. Between-patient variability was 19.6%, 15.6%, and 21.7% for CL, Vc, and Vp, respectively. A combined additive/proportional error model was used to describe residual variability, with a coefficient
of variation of 23.7% for the proportional component and a standard deviation of 0.0410 μg/ml for the additive component.
Significant patient-specific factors on CL were calculated CrCL, body weight, and to a lesser extent alanine transaminase
and folate deficiency. Gender and body weight were significant factors on Vc while both body surface area and albumin were significant factors on Vp. In conclusion, population pharmacokinetic modeling revealed relationships between pharmacokinetic parameters and various
patient specific factors.
Received: 18 November 1999 / Accepted: 28 March 2000 相似文献
2.
Boucaud M Pinguet F Culine S Poujol S Astre C Gomeni R Bressolle F 《Oncology research》2003,13(4):211-219
The purpose of this study was to develop a pharmacokinetic model simultaneously accounting for topotecan concentrations in plasma and saliva. Thirteen patients with metastatic epithelial ovarian cancer received topotecan. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Data were analyzed using the nonlinear mixed-effect model program. The saliva concentrations were associated to a peripheral compartment while the central compartment described the plasma concentration time course. Thus, a three-compartment model was used; the basic parameters were: total clearance (CL), initial volume of distribution (V1), transfer rate constants (k12/k21 and k13/k31). The interoccasion variability was taken into account in the model. Data analysis was performed using a three-step approach; in step 2, a close relationship was found between creatinine CL and topotecan CL. The inclusion of this second stage model significantly improved the fit. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 10.4 to 23 L/h) while interoccasion variability was limited (6%). Seven additional courses were used for model validation. A limited sampling strategy using Bayesian estimation based on two sampling times (saliva at 25 min and plasma plus saliva at 8.5 h after the start of infusion) was developed. This study shows that salivary concentrations can be effectively used for drug monitoring. 相似文献
3.
Léger F Loos WJ Fourcade J Bugat R Goffinet M Mathijssen RH Verweij J Sparreboom A Chatelut E 《British journal of cancer》2004,90(2):343-347
The aim of this study was to characterise the pharmacokinetics of the anticancer agent topotecan, and explore the influence of patient covariates and interoccasion variability on drug disposition. Data were obtained from 190 patients who received the drug as a 30-min infusion (N=72) or orally (N=118). The population model was built with the use of NONMEM to identify candidate covariates, and obtain models for clearance (CL) and volume of distribution. The final models were based on first-order absorption with lag-time (oral data), and a two-compartment model with linear elimination from the central compartment. The Cockcroft-Gault creatinine clearance (CrCl) and WHO performance status (PS) were the only significant covariates: CL=(12.8+2.1 x CrCl) x (1-0.12 x PS). For the volume of distribution, a correlation was found between body weight and the central volume (V1)=0.58 x body weight. Based on the structural models, a limited-sampling strategy was developed with minor bias and good precision that can be applied a posteriori using timed samples obtained at 1.5, and 6 h after the administration of topotecan. In conclusion, a population pharmacokinetic model for topotecan has been developed that incorporates measures of renal function and PS to predict CL. In combination with drug monitoring, the limited sampling strategy allows individualised treatment for patients receiving oral topotecan. 相似文献
4.
Moore JD Dezube BJ Gill P Zhou XJ Acosta EP Sommadossi JP 《Cancer chemotherapy and pharmacology》2000,46(3):173-179
The pharmacokinetics of TNP-470 and its major metabolites were investigated in AIDS patients enrolled in a phase I dose escalation
trial for the treatment of Kaposi's sarcoma. The patients received TNP-470 by 1-h intravenous infusion in dose cohorts of
10, 20, 30, 40, 50 and 70 mg/m2. The parent drug and metabolites, MII and MIV, were measured by high-performance liquid chromatography/mass spectrometry
(HPLC/MS) in plasma samples collected during and out to 168 h after the beginning of the infusion. Both metabolites were detected
in all patients' plasma, while the parent drug was undetectable at time-points as early as 5 min after the end of infusion
for some patients. A large interpatient variability of pharmacokinetic parameters among the dosing cohorts was observed for
TNP-470, with a mean (±SD) plasma elimination half-life (t1/2) of 0.06 ± 0.04 h, plasma clearance (CL) of 1487 ± 1216 l/h and an area under the concentration versus time curve (AUC) of
49.9 ± 35.8 ng/ml · h. Time to maximum plasma concentration (Tmax) typically occurred before the end of the infusion. The
predominant plasma metabolite was MII with a t1/2 of 1.21 ± 0.43 h, AUC of 1226 ± 2303 l/h and a Tmax occurring between 5 and 15 min after infusion. The reported active metabolite
MIV had a t1/2 of 0.24 ± 0.13 h, AUC of 24.9 ± 32.6 ng/ml · h and a Tmax occurring between the midpoint of the infusion and 15 min after
infusion. The parent drug was undetectable by HPLC/MS/MS in urine samples collected and pooled between 0–6 and 6–24 h from
the beginning of drug administration. Metabolite MIV was present in the 0–6-h urine pool of two patients enrolled in the highest
dosing cohorts, equivalent to 0.4% of the administered dose. Metabolite MII was present in all 0–6-h samples analyzed and
represented 1.12 ± 0.9% of the administered dose. Renal clearance (CLR) for MII was 140 ± 70 ml/h.
Received: 16 September 1999 / Accepted: 5 April 2000 相似文献
5.
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
6.
Rosing H Lustig V van Warmerdam LJ Huizing MT ten Bokkel Huinink WW Schellens JH Rodenhuis S Bult A Beijnen JH 《Cancer chemotherapy and pharmacology》2000,45(3):213-218
Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m2 with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The
mean area under the curve (AUC) for docetaxel was 3.1 ± 0.9 h · mg/l and the clearance was 34.8 ± 9.3 l/h per m2. There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected
in plasma samples collected 5–30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently
present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression
analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase
levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil
count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid
retention (grade 2–3) after two to five courses.
Received: 26 March 1999 / Accepted: 7 September 1999 相似文献
7.
Ashraf Montazeri Stéphane Culine Brigitte Laguerre Frédéric Pinguet Fran?ois Lokiec Nicolas Albin Alain Goupil Régine Déporte-Féty Roland Bugat Pierre Canal Etienne Chatelut 《Clinical cancer research》2002,8(2):394-399
PURPOSE: To take into account relationships between topotecan area under the plasma concentration (AUC) versus time curve and percentage decrease of neutrophil count previously shown when topotecan is administered on a 5-day, daily schedule. A multicentric clinical trial with individualized dosing of topotecan was performed in patients with platinum-refractory ovarian cancer. The primary goal of this study was to evaluate the toxicity of topotecan when the interindividual variability in plasma drug exposure is decreased. EXPERIMENTAL DESIGN: A total of 39 patients were evaluable. In cycle 1, the daily dose for the last 2 days was dependent on the observed topotecan AUC at day 1; the general objective was to constrain the overall AUC (i.e., from day 1 to day 5) within 37,500-75,000 nM.min. A pharmacokinetic study was also performed on day 5 of cycle 1 and day 1 of cycle 2 to evaluate the intrapatient pharmacokinetic variability both within cycle 1 and between cycles. RESULTS: The dose of topotecan was decreased for 20 patients and increased for only 1 patient within cycle 1. The total administered dose was correlated to the creatinine clearance. The dose adjustments allowed control of the topotecan exposure: mean (+/-SD) observed AUC of 70,697 (+/-12,364) nM.min. Fourteen cases of dose-limiting toxicity were observed, mainly in patients who previously received two different regimens of chemotherapy without a washout period before topotecan treatment. An overall response rate of 21% was observed in the 33 patients evaluable. CONCLUSION: Dose adjustments are required not only in patients with creatinine clearance below 40 ml/min, but also in those with values between 40 and 60 ml/min (recommended starting dose is 1.2 mg/m(2)). By performing drug monitoring and taking into consideration the past treatment of each patient, better dose individualization can be obtained. 相似文献
8.
Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors 总被引:2,自引:2,他引:0
William C. Zamboni Laura C. Bowman Ming Tan Victor M. Santana Peter J. Houghton William H. Meyer Charles B. Pratt Richard L. Heideman Amar J. Gajjar Alberto S. Pappo Clinton F. Stewart 《Cancer chemotherapy and pharmacology》1999,43(6):454-460
Purpose: Evaluation of inter- and intrapatient variability of topotecan oral bioavailability and disposition was performed in children
with malignant solid tumors. Patients and methods: Topotecan i.v. formulation was given orally on schedules of daily for 21 consecutive days (d × 21) or daily for 5 days per
week for 3 weeks [(d × 5)3], in both cases repeated every 28 days. Topotecan doses of 0.8 and 1.1 mg/m2 per day were evaluated on both schedules. Serial plasma samples were obtained after oral and i.v. administration of topotecan
at the beginning and end of the first course of therapy. Topotecan lactone and total concentrations were measured by a high-performance
liquid chromatography (HPLC) assay, and a one-or two-compartment model was fit to the plasma concentration-time data after
oral or i.v. administration, respectively. Topotecan oral bioavailability (F) was calculated as the ratio of the AUC determined
after oral treatment (AUCpo) divided by the AUC calculated after i.v. administration. Results: Pharmacokinetics studies were performed on 15 and 11 patients receiving 0.8 and 1.1 mg/m2 per day, respectively. After oral administration the topotecan lactone AUCpo and F determined for 0.8 and 1.1 mg/m2 per day were 13.6 ± 5.8 and 25.1 ± 12.9 ng ml−1 h and 0.34 ± 0.14 and 0.34 ± 0.16, respectively. The within-patient variance for AUCpo and F was much smaller than the between-patient variance. The ratio of topotecan lactone to total concentration was consistently
higher after oral as compared with i.v. administration. Conclusions: Large interpatient variability was noted in topotecan pharmacokinetics, whereas intrapatient variability was relatively
small. Further studies of oral topotecan are warranted to evaluate the tolerance of shorter courses and to define further
the interpatient variability.
Received: 14 August 1998 / Accepted: 9 November 1998 相似文献
9.
Françoise Bressolle Jean M. Joulia Frédéric Pinguet Marc Ychou Cécile Astre Jacqueline Duffour Roberto Gomeni 《Cancer chemotherapy and pharmacology》1999,44(4):295-302
Purpose: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients
with advanced colorectal cancer using circadian change kinetics. Methods: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m2) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m2) and then continuous infusion (600 mg/m2) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed
by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using
the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with
zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations
were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of
the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component
(over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second
periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters
(65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine
as covariables. Results: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean
clearance (CL
mean
) and initial volume of distribution (V), were as follows: the male subgroup showed a CL
mean
value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of
20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic
parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations
of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations
were compared with the predicted ones. Conclusion: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional
to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result
in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops
a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients.
Received: 21 September 1998 / Accepted: 20 January 1999 相似文献
10.
Tranchand B Amsellem C Chatelut E Freyer G Iliadis A Ligneau B Trillet-Lenoir V Canal P Lochon I Ardiet CJ 《Cancer chemotherapy and pharmacology》1999,43(4):316-322
Etoposide (VP16), a widely used anticancer drug, is a topoisomerase II inhibitor. A number of studies have highlighted a
correlation between hematologic toxicity and pharmacokinetic or physiological parameters. Other studies have also suggested
that the anti-tumor response could be related to the plasma etoposide concentration. Therefore, it would seem of interest
to individualize VP16 dose regimens on the basis of pharmacokinetic parameters. The aim of this study was to develop and validate
a limited-sampling strategy allowing VP16 pharmacokinetic evaluation with minimal disturbance to the patient. A total of 34
patients (54 kinetics) received VP16 at various dose regimens, with doses ranging between 30 and 200 mg and infusion times
varying between 0.5 and 2 h. The statistical characteristics of the pharmacokinetic parameters were assessed from the first
courses of treatment performed in 23/34 patients; then the following three-sample protocol was designed: the end of the infusion
and 5 and 24 h after the start of the infusion. For validation of the model the main pharmacokinetic parameters (clearance,
half-lives, volume of distribution) were estimated in the 11 remaining patients by maximum-likelihood estimation (ML) and
by Bayesian estimation (BE) using the three sampling times designed. Statistical comparison showed a good concordance between
ML and BE estimates (the bias for clearance was –1.72%). The limited-sampling strategy presented herein can thus be used for
accurate estimation of VP16 pharmacokinetic parameters.
Received: 17 November 1997 / Accepted: 25 August 1998 相似文献
11.
Akhtar S Beckman RA Mould DR Doyle E Fields SZ Wright J 《Cancer chemotherapy and pharmacology》2000,46(3):204-210
Purpose: The purpose of this randomized, two-period crossover study was to determine the pharmacokinetics of orally administered
topotecan in the presence and absence of oral ranitidine. Methods: Patients with solid malignant tumors refractory to standard treatment were given topotecan orally on a daily times five
schedule repeated every 21 days. Topotecan was given initially at 2.3 mg/m2 per day; dose adjustments were permitted after the first dose of course 2 if necessary. Blood samples for pharmacokinetic
assessments were drawn at protocol-specified times for up to 10 h following oral administration of topotecan on day 1 of courses
1 and 2. Patients were randomly assigned to receive a total of nine doses of ranitidine: 150 mg twice daily for 4 days before
day 1 of one of the first two courses and 150 mg given 2 h before the first topotecan dose. Plasma samples were assayed for
concentrations of active topotecan lactone (TPT-L) and total topotecan (TPT-T, lactone plus open-ring carboxylate form) using
high-performance liquid chromatography with fluorescence detection. After completion of courses 1 and 2, patients could continue
on therapy for days 1–5 of every 21 days if not withdrawn due to unacceptable toxicity, disease progression, protocol violation,
or by request. Patients continued on treatment for a maximum of six courses. Results: No pharmacokinetic parameter for either TPT-L or TPT-T differed significantly during administration of topotecan with ranitidine
compared with topotecan alone (n=13). Geometric mean ratios (95% confidence intervals, CIs) of areas under the curve in the presence and absence of ranitidine
were 0.94 (0.80, 1.10) for TPT-L and 0.97 (0.80, 1.16) for TPT-T. Corresponding ratios (CIs) of peak plasma concentrations
in the presence and absence of ranitidine were 1.06 (0.78, 1.44) for TPT-L and 1.07 (0.84, 1.38) for TPT-T. The median difference
in time to peak plasma concentration was 0.0 h for TPT-L and −0.5 h for TPT-T (i.e. slightly faster in the presence of ranitidine).
Conclusions: Administration of ranitidine prior to oral topotecan resulted in a similar extent of absorption. A slightly faster rate
of absorption of topotecan was also observed, which is unlikely to be of clinical significance. Dosage adjustments of orally
administered topotecan should not be necessary in patients who are pretreated with ranitidine, an H2 antagonist, or another
agent that comparably raises gastric pH.
Received: 8 September 1999 / Accepted: 5 April 2000 相似文献
12.
Laurent Nguyen Etienne Chatelut Christine Chevreau Brigitte Tranchand Isabelle Lochon Jean-Marc Bachaud André Pujol Georges Houin Roland Bugat Pierre Canal 《Cancer chemotherapy and pharmacology》1997,41(2):125-132
A population pharmacokinetics study using the NONMEM program was undertaken to determine the effects of different covariates
on the pharmacokinetic parameters of etoposide. A total of 1,044 plasma etoposide concentrations were determined by high-performance
liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25–85 years) treated for various tumor types with
i.v. (57 pts) or oral (43 pts) etoposide. For 67 pts, etoposide plasma protein binding was determined by equilibrium dialysis;
the unbound fraction ranged from 4% to 24%. A linear two-compartment model with first-order absorption (for oral dosing) accurately
described the concentration versus time data. The central and peripheral volumes of distribution were significantly correlated
with the body surface area [Vc (L) = 5.5 × BSA (m2) and Vp = 4.1 × BSA], but even after BSA had been taken into account, the interindividual variability of the two volumes
remained high (34% and 57%, respectively). The clearance (CL) was not correlated with the following covariates: age, BSA,
sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 × (1 − 0.009 × PRO) ×
WT/Scr + 33.8 × (1 − 0.29 × META) × (1− (1 − 0.012 × ALB), where ALB
,
PRO
,
WT
,and Scr, respectively, were albuminemia, proteinemia (g/l), weight (kg), and serum creatinine (μM ) and META = 1 if the patient had liver metastases (otherwise, META = 0). The interindividual variability in CL (mean value
30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bioavailability was
66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negatively
correlated with Scr but was not dependent on either PRO or ALB. These data show that modifications in PRO levels do not directly
affect plasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates
such as Scr in etoposide dosing. This population data base will constitute the prerequisite for adaptative control with feedback
dosing for continuous oral administration of etoposide.
Received: 12 January 1997 / Accepted: 9 June 1997 相似文献
13.
Hiroaki Okamoto Akira Nagatomo Hideo Kunitoh Hiroshi Kunikane Koshiro Watanabe 《Cancer chemotherapy and pharmacology》1998,42(4):307-312
Purpose: Carboplatin doses can be individualized using the formula of Calvert et al. (Calvert formula) dose (mg) = area under the
plasma concentration versus time curve (AUC) · [glomerular filtration rate (GFR) + 25]. Creatinine clearance (Ccr), either
measured by the 24-h method or calculated by the formula of Cockcroft and Gault [Cockcroft-Gault (CG) formula], is often substituted
for the GFR. The CG formula is based on patient weight, age and sex, and the serum creatinine (Cr) concentration. Another
method for predicting carboplatin clearance (CL) using patient characteristics has also been proposed by Chatelut et al. (Chatelut
formula). This study was undertaken to evaluate the performance of the three formulae in predicting standard- and low-dose
carboplatin pharmacokinetics. Methods: A total of 52 patients with advanced lung cancer were enrolled in this pharmacokinetic study; 37 received standard-dose
carboplatin and 25 received low-dose carboplatin. The Cr concentration was measured using an enzymatic assay. The three formulae
were used to predict carboplatin CL. The median absolute percent error (MAPE) for each formula was evaluated by comparing
the calculated and observed CL. For comparison of AUCs, free platinum plasma concentrations were measured at intervals up
to 24 h after carboplatin administration. AUCs were determined and compared with predicted values. Results: In the standard-dose carboplatin group, the MAPEs for the prediction of carboplatin CL from the 24-h Calvert, CG-Calvert
and Chatelut formulae were 13%, 12% and 23%, respectively. In the low-dose carboplatin group, the corresponding MAPEs were
27%, 18% and 44%, respectively. Observed standard-dose carboplatin AUCs after aiming for target AUCs of 5 and 6 mg · min/ml
using the Calvert formula based upon the 24-h Ccr were 5.3 ± 0.8 and 5.9 ± 0.8, respectively, indicating a small and acceptable
bias compared with that predicted from the dosing formula. Conclusions: The pharmacokinetics of standard-dose carboplatin were accurately predicted by the Calvert formula based upon either 24-h
or CG-calculated Ccr, but not by the Chatelut formula. Either CG-calculated or 24-h Ccr can be substituted for the GFR in
the Calvert formula for the determination of individual doses. The poor predictability of the Chatelut formula found in this
study might be the result of a differences in either the Cr assay or the patient population. Therefore, formulae which attempt
to estimate GFR are not necessarily valid if either the Cr assay or the patient population is changed.
Received: 23 July 1997 / Accepted: 16 December 1997 相似文献
14.
P. Guillet S. Monjanel A. Nicoara F. Duffaud B. Lacarelle D. Bagarry-Liegey A. Durand J. Catalin R. Favre 《Cancer chemotherapy and pharmacology》1997,40(2):143-149
Carboplatin (CBDCA), an analogue of cisplatin, exhibits reduced toxicity but wide interpatient variability of its pharmacokinetic
parameters. Individualization of the CBDCA dose is therefore necessary. Although various formulas have been developed for
this purpose, major side effects have been reported on CBDCA administration by short-term infusion (0.5 or 1h). We therefore
propose a new schedule of CBDCA administration. Instead of a dosing method based on the estimation of renal function when
a classic administration schedule is used, we propose a pharmacokinetic dosing method (Bayesian method), whereby CBDCA is
given by continuous infusion for 120 h. First, CBDCA was given to 21 patients to determine the population pharmacokinetic
parameters of carboplatin. Then, on the basis of total platinum plasma concentration measurements and Bayesian estimation
of pharmacokinetic parameters, it was possible to individualize the CBDCA dose within the first 24 h of the infusion. This
new protocol for CBDCA administration was evaluated in 36 new patients (60 courses). Three theoretical end points at the end
of the infusion were considered. For a given theoretical end point, 20 courses were taken into account. The theoretical end
points (i.e., 1, 1.5, and 1.8 mg/l) were compared with the concentrations measured at the end of the infusion, which were
0.99 ± 0.10, 1.41 ± 0.13, and 1.72 ± 0.20 mg/l, respectively. This Bayesian dosing method can easily be used in clinical practice,
and the determination of predictive performances has shown that the method is precise and unbiased. With no more toxicity
or practical difficulties than those produced by other methods, and with acceptable tolerance, it was possible to reach a
median dose that was 20% higher than the usual dose (484 ± 190 mg/m2 as compared with 400 mg/m2). In conclusion, this new schedule of CBDCA administration appears to be interesting in terms of tolerance. However, new
studies are required to confirm that this new scheme leads to equal or better efficacy than the classic protocol.
Received: 10 December 1995 / Accepted: 15 December 1996 相似文献
15.
Tkaczuk KH Zamboni WC Tait NS Meisenberg BR Doyle LA Edelman MJ Hausner PF Egorin MJ Van Echo DA 《Cancer chemotherapy and pharmacology》2000,46(6):442-448
Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor,
have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the
overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of
DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2,
4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.)
on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h
for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort
II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80
and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two
patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in
cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary
metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial
response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of
12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC
given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on
day 4 and TOPO on days 1–4 is not recommended.
Received: 18 February 2000 / Accepted: 19 July 2000 相似文献
16.
Supko JG Lynch TJ Clark JW Fram R Allen LF Velagapudi R Kufe DW Eder JP 《Cancer chemotherapy and pharmacology》2000,46(4):319-328
Purpose: The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly
and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical
antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients
by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically confirmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m2 (0.5 mg/m2 daily) according to a modified Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the
maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study
due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institute's
Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal
region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over five dose levels ranging from 2.5 to
17.5 mg/m2. Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m2 was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of
the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion.
There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were
defined in 14 patients during the first cycle of therapy. The RIA-detectable species exhibited apparent first-order pharmacokinetics
across the entire range of doses. The mean ± SD of the observed steady-state blood concentration at the 12.5 mg/m2 MTD was 282 ± 7 nM (n=3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 ± 4.3 h (n=14) in all patients. Mean values (n=14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 ± 0.09 l/h/m2 and 9.9 ± 3.3 l/m2, respectively. Conclusions: The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular
toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas
myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data
acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing
this compound into disease-oriented efficacy studies is merited.
Received: 8 November 1999 / Accepted: 28 April 2000 相似文献
17.
W C Zamboni M J Egorin D A Van Echo R S Day B R Meisenberg S E Brooks L A Doyle N N Nemieboka J M Dobson N S Tait K H Tkaczuk 《Journal of clinical oncology》2000,18(18):3288-3294
PURPOSE: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration. PATIENTS AND METHODS: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL(DOC)) and topotecan (CL(TPT)) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL(DOC) and CL(TPT) were calculated using compartmental methods. RESULTS: Mean +/- SD CL(DOC) in cycles 1 and 2 were 75.9 +/- 79.6 L/h/m(2) and 29.2 +/- 17.3 L/h/m(2), respectively (P: <.046). Mean +/- SD CL(TPT) in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P: >. 05). Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6, 738/microL and 2,808 +/- 4,518/microL, respectively (P: =.02). CONCLUSION: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia. 相似文献
18.
Delord JP Umlil A Guimbaud R Grégoire N Lafont T Canal P Bugat R Chatelut E 《Cancer chemotherapy and pharmacology》2003,51(2):127-131
The objective of this study was to explore correlations between a variety of covariates and oxaliplatin ultrafilterable and blood pharmacokinetic parameters. Data from 40 patients receiving oxaliplatin combined with 5-fluorouracil and levofolinic acid as standard treatment for advanced colorectal cancer were analysed. Plasma ultrafilterable, blood, and urine platinum concentrations were determined by flameless atomic absorption spectrophotometry. Data were analysed according to a population pharmacokinetic method using the NONMEM program. The best fit for oxaliplatin plasma ultrafilterable clearance (CL) was given by the following equation, which considers four covariates: body surface area (BSA, in metres squared), age (in years), sex (0 if male, 1 if female), and serum creatinine (Scr, in micromoles per liter): CL (l/h)=5.49xBSA+4.55xBSAx(140-AGE)x(1-0.15xSEX)/Scr. By taking into account these covariates, the interindividual variability in CL decreased from 43% to 33%. Renal clearance represented 34% of the overall elimination. This value was obtained by recovering urine over only 5 h from the beginning of the infusion and modelling the data using NONMEM. We would recommend the use of this methodology for pharmacokinetic studies in oncology in which renal clearances of the drug are presently rarely explored. The oxaliplatin blood concentrations versus time observed during the three-cycle period were well-described by a three-compartment model with first-order elimination from the central compartment. No significant intrapatient pharmacokinetic variability was observed between cycles. The relationship we obtained using the population approach between oxaliplatin CL and covariates may allow rational reduction of oxaliplatin dose in cases of elevated serum creatinine levels. 相似文献
19.
Turner PK Iacono LC Panetta JC Santana VM Daw NC Gajjar A Stewart CF 《Cancer chemotherapy and pharmacology》2006,57(4):475-482
Purpose: To develop and validate a pharmacokinetic limited sampling model (LSM) for intravenous and oral topotecan pharmacokinetic
studies in children. Methods: Topotecan lactone concentration-time data from five trials were used to develop and validate LSM for intravenous and oral
topotecan. Based on full sampling from one intravenous study (30 patients; 195 studies), a LSM for intravenous topotecan was
determined using a modification of the D-optimality algorithm. For oral topotecan we used full sampling data from one oral
topotecan study (27 patients; 47 studies) to develop an LSM. Accuracy and bias of each LSM were determined relative to the
full sampling method. Predictive performance of the LSM was validated using additional data and Monte–Carlo simulations based
on these data. Results: LSM for intravenous topotecan includes: 5 min, 1.5, and 2.5 h after the end of the 30 min infusion. The median accuracy
(absolute predicted error) and bias (predicted error) are ≤8% and ≤6.1%, respectively. For oral topotecan, the optimal LSM
includes: 15 min, 1.5, and 6 h. The median accuracy and bias are 6% and 4%, respectively. Conclusions: Our results indicate that the optimal sampling times for the intravenous LSM for topotecan in children consist of: predose,
and 5 min, 1.5, and 2.5 h after the end of infusion. For oral topotecan the sample times are predose, 15 min, 1.5, and 6 h
after dose administration. These LSM are invaluable to children receiving topotecan because it minimizes inconvenience and
blood collection.
Supported in part by US Public Health Service award CA23099 and the American Lebanese Syrian Associated Charities (ALSAC). 相似文献
20.
A pharmacokinetic model and the clinical pharmacology of cis-platinum, 5-fluorouracil and mitomycin-C in isolated pelvic perfusion 总被引:2,自引:0,他引:2
Purpose: An isolated pelvic perfusion technique using multiple agents was used both in patients with unresectable recurrent pelvic
neoplasms and as a preoperative therapy for advanced pelvic malignancy. Methods: The technique consisted of vascular occlusion via transfemoral balloon catheters, circulation and drug infusion using standard
hemodialysis technology, and a 45-min isolation period. Blood and urine samples were analyzed for the levels of cis-platinum
(17 patients, 21 courses of therapy, 50–100 mg/m2, infusion 0–10 min), 5-fluorouracil (12 patients, 14 courses, 1500 mg/m2, infusion 1/3 dose 0–1 min, 2/3 dose 1–20 min) and mitomycin-C (11 patients, 14 courses, 10–20 mg/m2, infusion 10–20 min). An empirical, four-compartment pharmacokinetic model was developed to establish drug distribution curves
for the pelvic and systemic circulations and to yield valid estimates of the pharmacokinetic parameters. Results: Pelvic isolation of drug was demonstrated by the pelvic-systemic drug exposure ratios of 6.0:1 for cis-platinum, 8.4:1 for
5-fluorouracil and 9.0:1 for mitomycin-C. Isolation at the L3-4 interspace resulted in minor urine drug elimination during
isolation (cis-platinum 7.2% of drug, 5-fluorouracil 2.4% and mitomycin-C 2.5%). Because drug infusion was limited to the
first 20 min of isolation, drug levels at the end of the isolation period were reduced to the extent that no extracorporeal
drug removal mechanism was needed. Conclusion: These pharmacokinetic results indicate that this isolation technique has the potential to provide increased therapeutic
indices and is a suitable system for evaluating fast-acting highly toxic experimental drugs to human pelvic cancers which
are poorly responsive to conventional clinical protocols.
Received: 20 February 1998 / Accepted: 25 September 1998 相似文献