Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer |
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Authors: | Wei Peng Yong Apurva A Desai Federico Innocenti Jacqueline Ramirez Dale Shepard Ken Kobayashi Larry House Gini F Fleming Nicholas J Vogelzang Richard L Schilsky Mark J Ratain |
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Institution: | (1) Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL 60637, USA;(2) Department of Medicine, University of Chicago, Chicago, IL 60637, USA;(3) Cancer Research Center, University of Chicago, Chicago, IL 60637, USA |
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Abstract: | Purpose Etoposide is a widely used cytotoxic drug that is commercially available in both intravenous and oral formulations. High interpatient
pharmacokinetic variability has been associated with oral etoposide administration. Various strategies used in the past to
reduce such variability have not been successful. Hence, this study was designed to evaluate if pharmacokinetic modulation
of oral etoposide with ketoconazole could lead to a favorable alteration of etoposide pharmacokinetics, and to assess the
feasibility and safety of this approach.
Methods Thirty-two patients were treated with ketoconazole 200 mg daily with an escalating dose of oral etoposide starting at a dose
of 50 mg every other day. Pharmacokinetic samples were obtained during the first treatment cycle after the administration
of an oral etoposide and ketoconazole dose. Additional baseline pharmacokinetic studies of etoposide alone were performed
4 days prior to the first treatment cycle.
Results Dose limiting toxicities were neutropenia and fatigue. Ketoconazole increased the area under the plasma concentration–time
curve (AUC) of oral etoposide by a median of 20% (p < 0.005). Ketoconazole did not reduce the interpatient variability in etoposide pharmacokinetics. Pretreatment bilirubin levels
correlated with etoposide clearance (Spearman’s r = −0.48, p = 0.008). The maximum tolerated dose was etoposide administered at 50 mg daily and ketoconazole 200 mg qd for 3 of 5 weeks.
Conclusions Ketoconazole reduces the apparent clearance of oral etoposide, does not alter its toxicity profile and does not reduce interpatient
pharmacokinetic variability. Other methods to reduce the pharmacokinetic variability of oral etoposide are needed. |
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Keywords: | Pharmacokinetic modulation Etoposide Ketoconazole Drug interaction |
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