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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 161-167 
    Details
    ISSN: 1432-0843
    Keywords: Etoposide ; Pharmacology ; Breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m2, peak plasma concentration 5.6±2.5 μg/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R 2=0.77). All patients who had a day 1 AUC〉2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R 2=98.9%). The equation AUCpr=−0.376+0.631×C4h+0.336×C6h was validated on the test set with a relative mean predictive error of −0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685644
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  • 2
    Electronic Resource
    Electronic Resource
    Phase II trial of carboplatin (JM8) in treatment of patients with malignant mesothelioma (1986)
    Springer
    Cancer chemotherapy and pharmacology 18 (1986), S. 284-285 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Seventeen patients with malignant mesothelioma were treated in a phase II study with carboplatin, a cisplatin analogue without significant nephrotoxicity or neurotoxicity. The drug was given in a dose of 300–400 mg/m2 by i.v. infusion, repeating at 28-day intervals. One patient achieved a complete clinical and radiological remission of 15 months' duration, and a second patient achieved a partial response of 11 months' duration (overall response rate 12%; overall response rate in previously untreated patients 20%). Four other previously untreated patients achieved symptomatic relief. Treatment was well tolerated without severe side-effects. Carboplatin, like most other cytotoxic drugs, is active only in a small minority of patients with mesothelioma, but its ability to achieve occasional good reponses and frequent symptomatic relief, combined with low toxicity, may justify a short therapeutic trial in patients whose tumour is symptomatic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273404
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of carboplatin administered in combination with the bradykinin agonist Cereport (RMP-7) for the treatment of brain tumours (2000)
    Springer
    Cancer chemotherapy and pharmacology 45 (2000), S. 284-290 
    Details
    ISSN: 1432-0843
    Keywords: Key words Carboplatin ; Pharmacokinetics ; Cereport ; Clinical ; Brain tumour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Introduction: Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood–brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials. Methods: Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100–300 ng/kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls. Results: Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration–time curve (AUC) of 7 mg/ml*min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104–133% of target, Spearman rank correlation coefficient=0.71, P 〈 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106–189% of target). Conclusions: Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050042
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  • 4
    Electronic Resource
    Electronic Resource
    The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) (1985)
    Springer
    Cancer chemotherapy and pharmacology 14 (1985), S. 265-271 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100–550 mg/m2 in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40–200 μM. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t1/2α=49±9 min, t1/2β=739±209 min). 27%±2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6%±0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid. Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m2 CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m2) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r=0.69, P=0.02) These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00258131
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  • 5
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug CI-941 in the mouse: a guide for rational dose escalation in patients (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 8-14 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses 〉20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD10 value of 20 mg/kg (95% confidence limits; range, 19–21 mg/kg) and an LD50 value of 22 mg/kg (95% confidence limits; range, 21–23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD10 to the LD10 (20 mg/kg). The drug was rapidly cleared from the plasma (250–400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC=110 μM x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC=277 μM x min). Despite 80%–84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%–18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD10 in the mouse) of 5 mg/m2 CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 μM x min, is proposed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00258450
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  • 6
    Electronic Resource
    Electronic Resource
    Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 367-372 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m2 daily×3), bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose=4.5×(GFR+25), where GFR is the absolute glomerular filtration rate measured by 51Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean ± SD values (n=8) of 4.8±0.6 mg/ml x min, 94±21 min, 129±21 min, 20.1±5.41, 155±33 ml/min and 102±24 ml/min for the AUC, beta-phase half-life (t1/2β), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132±32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values ±SD (n=8) of: AUC=5.1±0.9 mg/ml x min, t1/2α=40±9 min, t1/2β=257±21 min, MRT=292±25 min, Vd=13.3±1.31, TCLR=46±9 ml/min and RCLR=17.6±6.3 ml/min when the drug was given alone and AUC=5.3±0.6 mg/ml x min, t1/2α=34±6 min, t1/2β=242±25 min, MRT=292±25 min, Vd=12.5±1.81, TCLR=43±6 ml/min and RCLR=13.4±3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposidebleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00435838
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 161-167 
    Details
    ISSN: 1432-0843
    Keywords: Key words Etoposide ; Pharmacology ; Breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean±SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m2, peak plasma concentration 5.6± 2.5 μg/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R 2=0.77). All patients who had a day 1 AUC 〉2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R 2=98.9%). The equation AUCpr=−0.376+ 0.631×C4h+0.336×C6h was validated on the test set with a relative mean predictive error of −0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050382
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  • 8
    Electronic Resource
    Electronic Resource
    A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve (1996)
    Springer
    Cancer chemotherapy and pharmacology 37 (1996), S. 429-434 
    Details
    ISSN: 1432-0843
    Keywords: Key words Carboplatin ; Pharmacokinetics ; Limited-sampling strategy ; AUC estimation ; Carboplatin AUC ; Single-sample assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050408
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  • 9
    Electronic Resource
    Electronic Resource
    Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 313-325 
    Details
    ISSN: 1573-8744
    Keywords: etoposide ; etoposide phosphate ; bioequivalence ; pharmacokinetics ; pharmacodynamics ; humans ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioequivalence of etoposide phosphate, a prodrug of etoposide, to etoposide was assessed in a randomized, crossover study in 29 patients with histologically established solid tumors that had failed conventional treatment. Cohorts of patients received one treatment course each of etoposide and etoposide phosphate which consisted of a 100 mg/m2 per day etoposide equivalent dose infused iv over 1 hr on a Day 1 to 5 schedule of treatment. The second course was administered 21 days later or on recovery of blood cell counts. Plasma and urine samples were collected over 24 hr on Day 1 of each course and assayed for etoposide content by a validated HPLC/UV method. Resulting data were subjected to noncompartmental pharmacokinetic analysis. Hematology profiles were obtained by collecting blood samples prior to the first course and twice a week after each course. The pharmacodynamics and pharmacokinetics of etoposide were virtually identical after the two treatments. The point estimates (90% confidence intervals) for nadir WBC, granulocytes, hemoglobin, and platelets expressed as % decrease from the baseline, and for the pharmacokinetic parameters, Cmax, and AUC0-∞, after intravenous etoposide phosphate relative to etoposide were 100% (96%, 105%), 97% (91%, 103%), 95% (82%, 109%), 95% (84%, 106%), 107% (101%, 113%), and 113% (107%, 119%), respectively. Therefore, etoposide phosphate is bioequivalent to etoposide based on pharmacokinetic and pharmacodynamic assessments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353515
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  • 10
    Electronic Resource
    Electronic Resource
    A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid (1996)
    Springer
    Investigational new drugs 14 (1996), S. 325-335 
    Details
    ISSN: 1573-0646
    Keywords: lometrexol ; lometrexol-toxicity ; lometrexol-clinical efficacy ; lometrexol and folic acid ; DDATHF
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194536
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