Improved method for the determination of 4′-epidoxorubicin and seven metabolites in plasma by high-performance liquid chromatography

Maessen, P.A.; Mross, Klaus; Pinedo, H.M.; Vijgh, W.J.F. van der

doi:10.1016/0378-4347(87)80127-5

Cited by 34 publications

(12 citation statements)

References 13 publications

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“…(mean residual time) -[infusion time (h)/2]. The pharmacokinetic parameters for DTX, EPI and epirubicinol at EPI/DTX 60/60 mg/m 2 were compared with those used in other pharmacokinetic studies of each drug as a single agent [14,15] .…”

Section: High-performance Liquid Chromatography To Determine Drug Conmentioning

confidence: 99%

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Dose Escalation Study of Epirubicin and Docetaxel in Patients with Advanced or Recurrent Breast Cancer

Ichinose

Hamada²,

Mitsuyama³

et al. 2008

Chemotherapy

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Background: Anthracyclines and taxanes are major cytotoxic drugs against breast cancer. To develop a combination of epirubicin (EPI) and docetaxel (DTX) in Japan, dose escalation and pharmacokinetic studies were performed in patients with advanced or recurrent breast cancer. Methods: Twenty patients received EPI (40, 50 or 60 mg/m²) as 5-min intravenous infusion, followed by DTX infusion (50 or 60 mg/m²) over 1 h in cohorts of 3–6 patients. The maximum tolerated dose (MTD) was defined during the first cycle when more than 2 of 3 or 3 of 6 patients suffered a dose-limiting toxicity (DLT). The DLT was based on febrile neutropenia (FN), prolonged neutropenia, thrombocytopenia and grade 3–4 nonhematological toxicity during the first cycle. Plasma sampling was performed to assess the pharmacokinetic study of these drugs. Results: The second level (EPI/DTX 50/50 mg/m²) was found to be a maximum tolerated dose because of a short duration of FN with no distress. Subsequently, the protocol was modified to permit a new DLT definition including FN lasting for more than 72 h. At the following levels of EPI/DTX 50/50, 50/60 or 60/60 mg/m², the dose escalation study revealed a high incidence of grade 4 neutropenia (100%) and FN (67%), which did not reach DLT. However, the safety committee decided not to go further because of too high an incidence of FN lasting 3 days, although a little less than 72 h. The pharmacokinetic study with a combination of EPI and DTX showed comparable blood levels of DTX and EPI in relation to those seen when given alone. Conclusion: For further evaluation, the recommended dose and schedule of this combination is EPI 60 mg/m² and DTX 60 mg/m², given every 3 weeks to patients without prior chemotherapy and EPI 50 mg/m² and DTX 50 mg/m² given to patients with prior chemotherapy, respectively. The pharmacokinetic study indicates no interaction between EPI and DTX.

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Section: High-performance Liquid Chromatography To Determine Drug Conmentioning

confidence: 99%

“…The method proposed by Vergniol et al [13] for the DTX assay was validated for the analysis. Concentrations of EPI and its metabolites, epirubicinol, were determined using high-performance liquid chromatography, according to Maessen et al [14] . The lower limit of quantitation was 3 ng/ml.…”

Section: High-performance Liquid Chromatography To Determine Drug Conmentioning

confidence: 99%

Dose Escalation Study of Epirubicin and Docetaxel in Patients with Advanced or Recurrent Breast Cancer

Ichinose

Hamada²,

Mitsuyama³

et al. 2008

Chemotherapy

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“…The calibration lines for all metabolites and EPI were linear from 1 to 100 ng/ml. This assay is validated with respect to sensitivity, specificity, within and between day variation and reproducibility, and different storage conditions according to GLP guidelines [12,13]. Dexverapamil and nordexverapamil (the main metabolite of dexverapamil) were determined using a HPLC assay with fluorescence detection [14].…”

Section: Patients and Drug Administrationmentioning

confidence: 99%

“…Assay EPI and its seven metabolites, including the two glucuronides epirubicin glucuronide (E-Glu) and epirubicinol-glucuronide (EOL-Glu), epirubicinol (EOL), and the four aglycons epirubicinol aglycon (AOLON), 7-deoxy-epirubicinol-aglycon (7d-AOLON), epirubicin aglycon (AON), and 7-deoxy-epirubicin aglycon (7d-AON), were measured in plasma samples using a sensitive and specific high-performance liquid chromatography (HPLC) assay [12]. The two glucuronides were isolated from the urine of a patient treated with EPI, the other metabolites were kindly provided by Pharmacia Upjohn, Milano, Italy, for analytical purposes.…”

Section: Patients and Drug Administrationmentioning

confidence: 99%

Alteration in Epirubicin Pharmacokinetics and Metabolism by Dexverapamil: Results from a Phase II Study in Patients with Metastatic Breast Cancer

Mross¹,

Kröger²,

Herbst³

et al. 1999

Oncol Res Treat

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Background: To study the effect of the resistance-modifying agent (RMA) dexverapamil on the pharmacokinetics and metabolism of epirubicin. Methods: Nine women with metastatic breast cancer who received epirubicin (120 mg/m 2 ) as a 0.25-hour infusion without dexverapamil during the first treatment cycle and with dexverapamil (12 × 300 mg p. o. every 6 h) during the third treatment cycle were monitored with frequent plasma samples up to 48 h postinfusion. Epirubicin and its metabolites and dexverapamil and its main metabolite nordexverapamil were measured using a reverse-phase high-pressure liquid chromatography assay. Results: The concomitant administration of dexverapamil resulted in an increase in mean (±SD) epirubicin clearance from 1,408 (610) ml/min/m 2 to 2,004 (1,696) ml/min/m 2 , a decrease in epirubicin exposure (area under the curve (AUC)) from 2,968 (1,219) mg × h/ml to 1,901 (494) mg × h/ml, and an increase of the volume of distribution at steady state from 1,436 (1,231) l/m 2 to 2,425 (1,340) l/m 2 . The mean residence time and the elimination half-life were not different. There was a significant increase of epiglucuronide and the 7-deoxy-aglycones. At the time of epirubicin administration mean dexverapamil and nordexverapamil plasma levels were 790±409 and 755 ± 274 ng/ml, respectively. Conclusion: Dexverapamil had a significant effect on the pharmacokinetics and metabolism of epirubicin. However, other than observed in previous studies of RMAs and cytotoxic drugs, dexverapamil did not increase but reduce the AUC of epirubicin and had no effect on its toxicity. These data suggest that the type of pharmacologic interaction between RMAs and cytotoxic drugs can differ depending on the particular compounds used in combination.

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“…Details of the HPLC method and of the analysis of the various pharmacokinetic parameters determined in this study, e.g. AUC, volume of distribution at steady state and plasma clearance, have been previously described (Maessen et al, 1987;Mross et al, 1990Mross et al, , 1993b. The methods that were to be used for analysis of P-gp and MDR1 mRNA expression in fine-needle tumour biopsies were immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) respectively.…”

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confidence: 99%

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

Lehnert

Mross²,

Schueller³

et al. 1998

Br J Cancer

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Summary Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase 11 trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m-2 i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 gg ml-1 h-1, P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 gM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, Cl 5-39%, s.e.,p 0.079). The remissions lasted 3, 8, 11 and 11 + months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.

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Improved method for the determination of 4′-epidoxorubicin and seven metabolites in plasma by high-performance liquid chromatography

Cited by 34 publications

References 13 publications

Dose Escalation Study of Epirubicin and Docetaxel in Patients with Advanced or Recurrent Breast Cancer

Dose Escalation Study of Epirubicin and Docetaxel in Patients with Advanced or Recurrent Breast Cancer

Alteration in Epirubicin Pharmacokinetics and Metabolism by Dexverapamil: Results from a Phase II Study in Patients with Metastatic Breast Cancer

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

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