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Clinical and Pharmacologic Study of the Farnesyltransferase Inhibitor Tipifarnib in Cancer Patients With Normal or Mildly or Moderately Impaired Hepatic Function

Wandena S. Siegel-Lakhai, Mirjam Crul, Peter De Porre, Steven Zhang, Ilsung Chang, Henk Boot, Jos H. Beijnen, Jan H.M. Schellens

From the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam; Faculty of Pharmaceutical Sciences, Division of Drug Toxicology, University Utrecht, Utrecht, the Netherlands; Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; and Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ

Address reprint requests to Wandena S. Siegel-Lakhai, PhD, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: wan.les{at}quicknet.nl

PURPOSE: This study explored the feasibility of treating patients with impaired hepatic function with tipifarnib. The safety profile, pharmacokinetics, and relationship between the pharmacokinetics and toxicities were evaluated.

PATIENTS AND METHODS: Patients with mildly or moderately impaired hepatic function (Child-Pugh classification) were treated with tipifarnib bid on days 1 to 5 of cycle 1. Further dosing was based on the individual day 5 pharmacokinetic data and absolute neutrophil count. For patients with normal hepatic function, tipifarnib was dosed on days 1 to 14, followed by 1 week of rest. For all patients, in subsequent cycles, tipifarnib was administered for 21 consecutive days out of every 28 days.

RESULTS: Twenty-eight patients were included in the normal (n = 16), mild (n = 9), and moderate (n = 3) impairment groups. The most important grade 3 to 4 hematologic toxicity was leukocytopenia/neutropenia, which was mostly observed in patients with moderate impairment. Common nonhematologic toxicities were fatigue, nausea, and vomiting. The pharmacokinetic data showed higher plasma concentrations of tipifarnib in patients with liver impairment compared with patients with normal hepatic function.

CONCLUSION: In patients with mildly impaired hepatic function, tipifarnib can be administered safely at a starting dose of 200 mg bid, but it is not safe to treat patients with moderate hepatic impairment.

Supported by Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium.

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

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