This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Johansen, M. Articles by Madden, T. Search for Related Content PubMed PubMed Citation Articles by Johansen, M. Articles by Madden, T.

Phase I Evaluation of Oral and Intravenous Vinorelbine in Pediatric Cancer Patients: A Report from the Children's Oncology Group

Authors' Affiliations: Divisions of ¹ Pharmacy and ² Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, Texas; ³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Arcadia, California; and ⁴ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Timothy Madden, Division of Cancer Medicine and Pharmacy, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 601, Houston, TX 77030; E-mail: tmadden{at}mdanderson.org.

Purpose: Vinorelbine (Navelbine) is an orally absorbable Vinca with broad antitumor activity. It differs from other Vinca in that it is structurally modified on the catharanthine nucleus and has differential actions on tubulin that render it less neurotoxic than other compounds in this class. We conducted a phase I study of vinorelbine given the activity of Vinca alkaloids in many pediatric tumors.

Experimental Design: We evaluated the safety and pharmacokinetics of oral and i.v. vinorelbine administered weekly x 6 in children (age, 2-17 years) with different tumors. Patients with disease involvement in the bone marrow were eligible but were stratified and dose-escalated separately. Oral vinorelbine (week 1) was administered as liquid-filled gelatin capsules at thrice the i.v. dose. Intravenous vinorelbine doses of 24 to 37.5 mg/m² were administered on weeks 2 to 6.

Results: The dose-limiting toxicity in patients without marrow involvement was reversible neutropenia. Common nonhematologic toxicities included grade 2 nausea/vomiting and increased hepatic transaminases. A higher mean i.v. Cl_TB was observed (1.75 ± 1.0 L/h/kg) compared with adult reports, with a mean t_1/2B of 16.5 ± 9.7 hours. Mean oral bioavailability was 28.5 ± 22.5%. The apparent oral clearance (12.1 ± 13.0 L/h/kg) and volume of distribution (69.4 ± 30.6 L/kg) were substantially higher than in adults given similar oral doses.

Conclusions: The maximum tolerated dose in children without bone marrow involvement was 30 mg/m², similar to that reported in adults, with myelosuppression being the dose-limiting toxicity. Higher plasma clearance resulted in lower area under the plasma concentration-time curves at a given dose compared with that reported in adults.