Premium
Safety and Pharmacokinetics of Sorafenib Combined With Capecitabine in Patients With Advanced Solid Tumors: Results of a Phase 1 Trial
Author(s) -
Awada Ahmad,
Gil Thierry,
Whenham Nicolas,
Hamme Julie,
BesseHammer Tatiana,
Brendel Erich,
Delesen Heinz,
Joosten Miranda C.,
Lathia Chetan D.,
Loembé Bienvenu A.,
PiccartGhebart Martine,
Hendlisz Alain
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010386226
Subject(s) - capecitabine , sorafenib , medicine , concomitant , pharmacokinetics , adverse effect , pharmacology , fluorouracil , chemotherapy , hepatocellular carcinoma , cancer , colorectal cancer
Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m 2 bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m 2 bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m 2 bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m 2 bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m 2 bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug‐related adverse events were hand‐foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose‐limiting toxicities in 6 patients. Sorafenib exposure (C max and AUC 0–12 ) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5‐fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m 2 bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m 2 bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5‐fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m 2 bid, as scheduled above.