A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of
vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma.
Author(s): Grippo JF(1), Zhang W, Heinzmann D, Yang KH, Wong J, Joe AK, Munster P, Sarapa N,
Daud A.
Affiliation(s): Author information:
(1)Hoffman La Roche, 340 Kingsland Street, Nutley, NJ, 07110, USA,
joseph.grippo@roche.com.
Publication date & source: 2014, Cancer Chemother Pharmacol. , 73(1):103-11
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.
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