Therapeutic monitoring of continuous infusion etoposide in small-cell lung cancer.

Joel, S P; Ellis, Paul; O’Byrne, Kenneth J.; Papamichael, D.; Hall, Matthew; Penson, R. T.; Nicholls, Stephen J.; O’Donnell, Chris; Constantinou, Andreas I.; Woodhull, J; Nicholson, M.; Smith, Ian; Talbot, D; Slevin, M. L.

doi:10.1200/jco.1996.14.6.1903

Cited by 24 publications

(14 citation statements)

References 30 publications

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“…This approach has yielded a decrease in intrapatient and interpatient variability in haematological toxicity in patients treated with i.v. etoposide [40,41]. TDM-guided dose individualization of methotrexate, teniposide and cytarabine has permitted the safe increase drug exposure in children with leukaemia [42], resulting in a signi®cant improvement in disease free as compared with conventional therapy.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of oral etoposide

Toffoli

Corona

Sorio

et al. 2001

Brit J Clinical Pharma

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“…This patient had a [5LCr]EDTA clearance, which was at the bottom of the normal range (59 ml min-' m-2) and the longest [5'Cr]EDTA elimination half-life (114 min vs 77±23 min), although no overt signs of renal impairment. It seems likely that the reduced interpatient pharmacokinetic variability seen in this group of patients was due to the fact that only one child had previously received cisplatin, as cisplatin therapy has previously been shown to predict for reduced etoposide clearance (Pfluger et al, 1987(Pfluger et al, , 1993Relling et al, 1994 Previous studies involving targeted dosing with etoposide using limited sampling methods have involved the administration of etoposide as a continuous infusion over 3 or 5 days (Ratain et al, 1989(Ratain et al, , 1991Joel et al, 1996). In addition, English et al (1996) reported two anephric paediatric patients in whom targeted dosing with both etoposide and carboplatin was possible using detailed pharmacokinetic sampling over three doses.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Joel et al (1996) have reported the results of a pharmacokinetically based dose escalation study of etoposide given intravenously as a continuous infusion over 5 days. Dose modifications after 18 and 66 h were performed on the basis of plasma etoposide concentrations in order to achieve a target level of 2, 3, 4 or 5 ,ug ml-'.…”

Section: Discussionmentioning

confidence: 99%

A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children

Lowis

Price²,

Pearson³

et al. 1998

Br J Cancer

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Summary Pharmacokinetically guided dosing was performed in nine paediatric patients receiving etoposide. Doses on day 2 of a 2-or 3-day schedule were adapted on the basis of the day-1 area under the plasma etoposide concentration vs time curve (AUC). The day-1 AUC was estimated using a limited sampling model and the day-2 target AUC defined by the etoposide dose-AUC relationship observed in 33 children. Target AUC values (4.6-8.2 mg ml-1 x min) were achieved with a high degree of precision and with little bias (mean error 11% and root mean squared error 15% respectively). Pharmacokinetic parameters were similar to those reported previously in children, although interpatient pharmacokinetic variability was less than that observed previously: plasma clearance, 23 (18-26) ml min-' m-2; volume of distribution at steady state (Vdss), 6.0 (3.9-8.9) m-2; t,,2 254 (127-550) min (median and range). This study has demonstrated that pharmacokinetically guided dosing with etoposide is feasible. However, pharmacokinetically guided dosing is likely to be of most benefit in patients with abnormalities of renal or hepatic function, or in children with prior exposure to cisplatin.Keywords: etoposide; adaptive dosing; pharmacokinetics; children Etoposide is an active and widely used agent in paediatnic oncology.

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“…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%

“…The initial infusion rate was calculated and adjusted according to measured plasma etoposide concentrations (Joel et al, 1996).…”

Section: à2mentioning

confidence: 99%

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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Therapeutic monitoring of continuous infusion etoposide in small-cell lung cancer.

Cited by 24 publications

References 30 publications

Population pharmacokinetics and pharmacodynamics of oral etoposide

Population pharmacokinetics and pharmacodynamics of oral etoposide

A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children

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

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