A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Joel, S.; O’Byrne, Kenneth J.; Penson, R. T.; Papamichael, D.; Higgins, Alexandra; Robertshaw, H.; Rudd, Robin; Talbot, Denis; Slevin, M. L.

doi:10.1023/a:1008437805286

Cited by 15 publications

(10 citation statements)

References 28 publications

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“…Etoposide is a cell‐cycle specific cytotoxic drug: the cells have to be exposed to it during the sensitive part of the cell cycle (late S‐phase) and exposure maintained for long enough to kill the cells. The therapeutic window is highly dependent on the duration of the infusion [9]. Duration above a certain threshold concentration was therefore found to be the best predictor of efficacy in small‐cell lung cancer.…”

Section: Systemic Exposure Indicesmentioning

confidence: 99%

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Rousseau

Marquet

2002

Fundamemntal Clinical Pharma

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Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin. carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration-time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued.

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Section: Systemic Exposure Indicesmentioning

confidence: 99%

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Rousseau

Marquet

2002

Fundamemntal Clinical Pharma

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“…For etoposide, a topoisomerase II inhibitor, haematological toxicity is closely related to unbound drug exposure [10,11]. Joel et al [12] hypothesized the existence of a therapeutic window, but further studies are needed to better de®ne the therapeutic concentration or exposure to etoposide.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of oral etoposide

Toffoli

Corona

Sorio

et al. 2001

Brit J Clinical Pharma

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Aims To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.Methods A prospective, open label, cross‐over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P‐Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.Results Mean clearance was 1.14 l h−1 (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r2 = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l−1 h; CV 64%; range 0.4–9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l−1 h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l−1 h) than in patients with stable (2.1 mg l−1 h) or progressive disease (2.3 mg l−1 h) (P = 0.01).Conclusions Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

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“…Etoposide phosphate infusions allow prolonged scheduling of etoposide with pharmacokinetic monitoring to allow dose adjustments. Trials in our unit over the past decade have shown this to be feasible and well tolerated (O'Byrne et al, 1997;Joel et al, 1998;Braybrooke et al, 2003). Experience from previous studies, together with the preclinical data presented here, led to the adoption of the sequential administration of topotecan for 5 days followed by EP for 5 days as a novel regimen to be investigated in this phase I study in patients with advanced ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…On the morning of day 7 (18 h after the start of the infusion) and on day 9 of each cycle, peripheral venous blood samples were drawn for determination of total plasma etoposide levels, as described previously (Harvey et al, 1985a;Joel et al, 1996Joel et al, , 1998. Plasma standards covering the range 0.5 -5.0 mg ml À1 were used; patient samples were run in duplicate, with quality control samples at two concentrations (1.25 and 3.5 mg ml À1 ).…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

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Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer

et al. 2005

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A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0 -2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m À2 day À1 days 1 -5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mg ml À1 . The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIa levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.

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A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Abstract: A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Cited by 15 publications

References 28 publications

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Population pharmacokinetics and pharmacodynamics of oral etoposide

Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer

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