Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors

Eric K. Rowinsky, Dennis A. Noe, Donald L. Trump, Eric P. Winer, V. Sol Lucas, William A. Wargin, John A. Hohneker, Barbara Lubejko, Susan E. Sartorius, David S. Ettinger, Ross C. Donehower

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Abstract

Purpose: The feasibility of administering vinorelbine (Navelbine, Burroughs Wellcome Co, Research Triangle Park, NC), a semisynthetic vinca alkaloid with broad activity, as a liquid-filled gelatin capsule was evaluated in a bioavailability (F) and pharmacokinetic study. Patients and Methods: Each of 17 cancer patients had pharmacokinetic studies performed after receiving vinorelbine 30 mg/m2 intravenously (IV), which is the maximum-tolerated dose (MTD) for weekly IV administration, and twice after receiving the oral formulation at a nominal dose of 100 mg/m2. Subsequently, these patients and 10 other subjects received the oral formulation at a dose of 100 mg/m2/wk to evaluate the feasibility of chronic oral administration. Results: Plasma drug disposition was well described by a triphasic model. Mean central volume of distribution and steady-state volume of distribution (V(ss)) were large (0.66 ± 0.46 L/kg and 20.02 ± 8.55 L/kg, respectively); the mean harmonic terminal half-life (t( 1/2 )) was long (18 hours); and the high mean clearance (Cl) rate (0.80 ± 0.68 L/h/kg) approached hepatic blood flow. F was low (0.27 ± 12), and absorption was rapid (mean time of maximum plasma concentration [T(max)], 0.91 ± 0.22 hours). Absorption parameters after the first and second oral doses were similar, with mean F values of 0.27 ± 0.14 and 0.25 ± 0.11, respectively. Coefficients of variability (CVs) for F, maximum plasma concentration (C(max)), and T(max) were 32%, 42%, and 78%, respectively, indicating moderate intraindividual variability. The pharmacologic profile of this oral formulation indicates that there is a large first-pass effect. Neutropenia was the principal toxicity of oral vinorelbine. Grade 3 or 4 neutropenia occurred in 63% of patients, but only 11% developed neutropenia and infection. Nausea, vomiting, and diarrhea were also common with oral administration, but these effects were rarely severe and could be ameliorated by using a divided-dose schedule and/or prophylactic antiemetic and antidiarrheal agents. The mean nominal oral dose was 82 mg/m2, and the mean percentage of intended dose that was received was 92%. Although dose escalations were permitted for negligible toxicity, doses were not escalated to greater than 100 mg/m2/wk in any patient. Vinorelbine given as a liquid-filled gelatin capsule at 100 mg/m2 provided equivalent pharmacologic exposure as 30 mg/m2 IV. Conclusion: The oral administration of vinorelbine, specifically as a liquid-filled, soft gelatin capsule, is a feasible route of administration. Weekly oral dosing at 100 mg/m2 induces a consistent degree of myelosuppression, but the high frequency of grade 3 or 4 neutropenia, albeit brief and uncomplicated, warrants the recommendation of a slightly lower starting dose, ie, 80 mg/m2/d, for subsequent phase II evaluations, especially in heavily pretreated patients.

Original languageEnglish (US)
Pages (from-to)1754-1763
Number of pages10
JournalJournal of Clinical Oncology
Volume12
Issue number9
DOIs
StatePublished - Sep 1994
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Rowinsky, E. K., Noe, D. A., Trump, D. L., Winer, E. P., Lucas, V. S., Wargin, W. A., Hohneker, J. A., Lubejko, B., Sartorius, S. E., Ettinger, D. S., & Donehower, R. C. (1994). Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors. Journal of Clinical Oncology, 12(9), 1754-1763. https://doi.org/10.1200/JCO.1994.12.9.1754