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A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma

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Abstract

Purpose

This study characterized the multiple-dose pharmacokinetics of vemurafenib 240–960 mg twice daily (bid) in BRAF V600E mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets).

Methods

Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2.

Results

Vemurafenib concentration increased with multiple doses to steady state at day 15; C max, AUC0–8h, and AUC0–168h increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240–960 mg bid. Day 15 mean accumulation ratios (ratio of AUC0–8h on day 15/AUC0–8h on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration–time profile throughout the bid dosing interval. During dose interruption (days 15–22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5–38.4 h.

Conclusions

Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C max) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

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Acknowledgments

The authors thank Drs. Daniels, Hallmeyer, and Gajewski for their participation in the study. Support for third-party editing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. The study was sponsored by F. Hoffmann-La Roche Ltd.

Conflict of interest

Joseph Grippo is an employee of Hoffmann-La Roche, received financial support for this research, and is a shareholder of Hoffmann-La Roche. Weijing Zhang is an employee of Hoffmann-La Roche and received financial support for this research. Dominik Heinzmann is an employee of Hoffmann-La Roche, received financial support for this research, and is a shareholder of Hoffmann-La Roche. Kuo-Hsiung Yang was a previous employee of Hoffmann-La Roche but has no current conflicts of interest. Jenny Wong is an employee of Hoffmann-La Roche and a shareholder of Hoffmann-La Roche. Andrew Joe was a previous employee of Hoffmann-La Roche but has no current conflicts of interest. Pamela Munster has received financial support for research projects from Merck. Nenand Sarapa is an employee of Hoffmann-La Roche, received financial support for this research, and is a shareholder of Hoffmann-La Roche. Adil Daud has served as a consultant to Merck and Amgen. Dr. Daud has also received financial support for research projects from Genentech/Roche, GSK, Merck, OncoSec, Novartis, and Pfizer.

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Author notes

  1. K. H. Yang

    Present address: UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA

  2. A. K. Joe

    Present address: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Authors and Affiliations

  1. Hoffman La Roche, 340 Kingsland Street, Nutley, NJ, 07110, USA

    J. F. Grippo, W. Zhang, K. H. Yang, J. Wong, A. K. Joe & N. Sarapa

  2. Hoffman La Roche, Basel, Switzerland

    D. Heinzmann

  3. UCSF, San Francisco, CA, USA

    P. Munster & A. Daud

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  1. J. F. Grippo
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Corresponding author

Correspondence to J. F. Grippo.

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Grippo, J.F., Zhang, W., Heinzmann, D. et al. A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma. Cancer Chemother Pharmacol 73, 103–111 (2014). https://doi.org/10.1007/s00280-013-2324-5

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  • DOI: https://doi.org/10.1007/s00280-013-2324-5

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