Predicting etoposide toxicity: relationship to organ function and protein binding.

Joel, Simon P.; Shah, Rita; Clark, Peter; Slevin, M. L.

doi:10.1200/jco.1996.14.1.257

Cited by 90 publications

(31 citation statements)

References 10 publications

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“…Our data con®rm the ®ndings of Joel, who studied the pharmacokinetics and dynamics of i.v. etoposide in patients with small cell lung cancer and found that protein binding and renal function in¯uence the toxicity of etoposide, by affecting the free drug exposure [11]. Although the model con®rms the importance of free drug exposure for toxicity, there remains a substantial interpatient variability in pharmacodynamics not explained by patient characteristics such as the performance status, pretreatment with chemotherapy or baseline white blood cell counts.…”

Section: Discussionmentioning

confidence: 98%

“…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%

“…Since etoposide is highly plasma protein bound [11,20], particular attention was given to the PK and PD of unbound etoposide.…”

Section: Introductionmentioning

confidence: 99%

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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: 98%

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetics and pharmacodynamics of oral etoposide

Toffoli

Corona

Sorio

et al. 2001

Brit J Clinical Pharma

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“…Four studies have demonstrated that mild-to-moderate liver dysfunction (bilirubin Ͼ1-2 mg/dl) does not affect etoposide PKs, but severe impairment (not clearly defined) can contribute to greater toxicity (myelosuppression, mucositis) because of reduced hepatobiliary metabolism [16 -19]. In addition, albumin levels have been identified as important, with a higher fraction of unbound etoposide being directly related to high serum bilirubin and low albumin, which can lead to greater hematological toxicity [20]. However, the pharmacologic effects may not be altered at all in those patients with hepatic dysfunction and hypoalbuminemia resulting from greater renal clearance [21].…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary

2007

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After completing this course, the reader will be able to:1. Describe the currently recommended dose adjustments for common chemotherapeutics in oncology patients with organ dysfunction.2. Explain the rationale for using phase I dose-escalation studies to determine appropriate chemotherapy dosing in patients with organ dysfunction.3. Discuss the limitations of the currently available studies to guide chemotherapy dose adjustment in patients with organ dysfunction.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThere are few prospective data regarding the pharmacokinetics and clinical toxicity of commonly used chemotherapeutics in cancer patients with organ dysfunction. Although increasing numbers of studies are investigating newer chemotherapeutics in patients with liver or kidney dysfunction, most guidelines for dosing, especially for established agents, remain empiric. This review describes the available data (both prospective and case study) evaluating the impact of renal and hepatic dysfunction on toxicity and dosing of commonly used chemotherapeutics and provides a practical summary for their use in this setting.

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“…Numerous attempts to define a priori dosage adjustments of etoposide has been made and predominantly such dosing algorithms base dosage on renal function [8,9] or hepatic function [10][11][12]. A more refined way to adjust dosing has been the application of a maximum a posteriori (MAP) Bayesian guided dosing, utilizing knowledge of the population distribution of the pharmacokinetic parameters for the drug [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

A tool for neutrophil guided dose adaptation in chemotherapy

Wallin

Friberg

Karlsson

2009

Computer Methods and Programs in Biomedicine

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c o m p u t e r m e t h o d s a n d p r o g r a m s i n b i o m e d i c i n e 9 3 ( 2 0 0 9 ) 283-291 j o u r n a l h o m e p a g e : w w w . i n t l . e l s e v i e r h e a l t h . c o m / j o u r n a l s / c m p b A tool for neutrophil guided dose adaptation in chemotherapyJohan E IntroductionNeutropenia is a major side-effect of many antitumor agents, and is often the dose-limiting factor [1] The risk of infection is related to the degree and duration of neutropenia [2,3]. Dose adjustment to minimize the risk of experiencing severe neutropenia could either be made a priori or a posteriori, ranging in complexity from body size based dosing up to utilization of statistical models and various sampling. In this paper we show implementation of a pharmacokinetic-pharmacodynamic model, describing the neutrophil concentrations after anti-cancer treatment, in a simple tool to be used in the patient care at the clinic. This tool would facilitate use of neutrophil data from the first completed course of treatment in a Bayesian maximum a posteriori process to guide dose selection in an upcoming course. Etoposide was chosen as a model substance, due to it being rather * Corresponding author at: Division of Pharmacokinetics and Drug Therapy, Biomedical Centre, Uppsala University, Sweden. Tel.: +46 18 471 4639; fax: +46 18 471 4003. E-mail address: johan.wallin@farmbio.uu.se (J.E. Wallin).well-characterized and its wide-spread use, and the access to a suitable validation dataset. A predictive model of myelosuppression could be used for dose individualization, in order to avoid neutropenia, a prolonged treatment interval and/or a suboptimal tumor effect. For etoposide current treatment guidelines state that occurrence of severe neutropenia should lead to a reduction or postponement of next dose until neutrophil recovery [4]. The dose reduction is not necessarily tailored to the patient, but usually by fixed decrements such as to 75% or 50% of the original dose. This leads to a one-sided dose adjustment, where only patients experiencing toxicity receives a dose change, but not necessarily in an optimal fashion. The possibility that patients experiencing only a minor myelosuppression are underexposed and might benefit from an increased dose is not taken into account. The relation between hematological toxicity and patient survival has been investigated in clinical 0169-2607/$ -see front matter

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Predicting etoposide toxicity: relationship to organ function and protein binding.

Abstract: Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients.

Cited by 90 publications

References 10 publications

Population pharmacokinetics and pharmacodynamics of oral etoposide

Population pharmacokinetics and pharmacodynamics of oral etoposide

Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary

A tool for neutrophil guided dose adaptation in chemotherapy

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