title: Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases.
abstract: Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL), suppresses bone resorption. This open-label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer-related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for > or = 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade < or = 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment-related; other treatment-related AE were grade < or = 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose-linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N-telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from -61.9% to -90.8%. No dose-limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non-Japanese populations.
authors.affiliation: National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. kyonemor@ncc.go.jp
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Koichi
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujii
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Arai
authors.forename: Winnie
authors.initials: W
authors.lastname: Sohn
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohkura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohtsu
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000652:urine; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D001862:Bone Resorption / Q000517:prevention & control; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D024042:Collagen Type I / Q000652:urine; D003404:Creatinine / Q000652:urine; D000069448:Denosumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007564:Japan; D008875:Middle Aged; D010455:Peptides / Q000652:urine; D053245:RANK Ligand / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D010455:Peptides; D053245:RANK Ligand; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D003404:Creatinine