Originally published as JCO Early Release 10.1200/JCO.2005.02.1295 on May 1 2006

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Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer

Mark Wong, Rosemary L. Balleine, Elaine Y.L. Blair, Andrew J. McLachlan, Stephen P. Ackland, Madhu B. Garg, Scott Evans, David Farlow, Michael Collins, Laurent P. Rivory, Janelle M. Hoskins, Graham J. Mann, Christine L. Clarke, Howard Gurney

From the Westmead Institute for Cancer Research Westmead Millennium Institute, Departments of Translational Oncology, Nuclear Medicine and Medical Oncology Sydney; Institute of Clinical Pathology and Medical Research, Westmead; Faculty of Pharmacy and Departments of Pharmacology and Medicine; Faculty of Medicine University of Sydney, Sydney; Department of Medical Oncology, Newcastle Mater Misericordiae Hospital, Waratah, Australia

Address reprint requests to Howard Gurney, MD, Department of Medical Oncology, Westmead Hospital, Westmead, NSW 2145, Australia; e-mail: howardg{at}westgate.wh.usyd.edu.au

PURPOSE: Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization.

PATIENTS AND METHODS: Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi (^99mTc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment.

RESULTS: There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P < .01) and hepatic ^99mTc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P < .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02).

CONCLUSION: Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.

Supported by a postgraduate medical scholarship from the National Health and Medical Research Council of Australia (M.W.) and S.A. and M.G. acknowledge support from Staff Specialists Trust Fund, Newcastle Mater Misericordiae Hospital.

M.W. and R.L.B. contributed equally to this article and share the first author designation.

The authors of this manuscript confirm that it contains original work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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