Factors affecting epirubicin pharmacokinetics and toxicity: Evidence against using body-surface area for dose calculation

Howard P. Gurney, Stephen Ackland, Val Gebski, Geoffrey Farrell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose. Patients and Methods: The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutrapenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression. Results: There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) far epirubicin correlated with prothrombin index (P < .01), anti-pyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, same of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined. Conclusion: These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.

LanguageEnglish
Pages2299-2304
Number of pages6
JournalJournal of Clinical Oncology
Volume16
Issue number7
Publication statusPublished - Jul 1998
Externally publishedYes

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Epirubicin
Body Surface Area
Pharmacokinetics
Neutropenia
Antipyrine
Liver Function Tests
Body Size
Transferrin
Bile Acids and Salts
Serum
Partial Thromboplastin Time
Liver
Prothrombin
Transaminases
Drug-Related Side Effects and Adverse Reactions
Linear Models
Creatinine

Cite this

@article{59399a798d544c799ab1c51defae50ce,
title = "Factors affecting epirubicin pharmacokinetics and toxicity: Evidence against using body-surface area for dose calculation",
abstract = "Purpose: An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose. Patients and Methods: The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutrapenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression. Results: There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) far epirubicin correlated with prothrombin index (P < .01), anti-pyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, same of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined. Conclusion: These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.",
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Factors affecting epirubicin pharmacokinetics and toxicity : Evidence against using body-surface area for dose calculation. / Gurney, Howard P.; Ackland, Stephen; Gebski, Val; Farrell, Geoffrey.

In: Journal of Clinical Oncology, Vol. 16, No. 7, 07.1998, p. 2299-2304.

Research output: Contribution to journalArticleResearchpeer-review

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T2 - Journal of Clinical Oncology

AU - Gurney, Howard P.

AU - Ackland, Stephen

AU - Gebski, Val

AU - Farrell, Geoffrey

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N2 - Purpose: An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose. Patients and Methods: The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutrapenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression. Results: There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) far epirubicin correlated with prothrombin index (P < .01), anti-pyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, same of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined. Conclusion: These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.

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