A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAFV600E mutation-positive metastatic melanoma

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 1; pp. 103 - 111
• Main Authors: Grippo, J. F., Zhang, W., Heinzmann, D., Yang, K. H., Wong, J., Joe, A. K., Munster, P., Sarapa, N., Daud, A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2014; Springer
• Subjects: Antineoplastic agents; Biological and medical sciences; Cancer Research; Dermatology; Medical sciences; Medicine; Medicine & Public Health; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Vemurafenib; Phase I; Pharmacokinetics; Melanoma; Dose proportional; Human; Malignant tumor; Metastasis; Multiple dose; Randomization; Malignant melanoma; Genetics; Advanced stage; Mutation; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2324-5

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 , AUC 0–8h , and AUC 0–168h 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 AUC 0–8h on day 15/AUC 0–8h 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.