title: A 4-week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys.
abstract: Trastuzumab is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 (HER2). Women with HER2-positive tumors have an increased risk of brain metastases. The blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and CSF following standard intravenous administration. To evaluate the potential of effects on the central nervous system, a 4-week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0, 3, or 15 mg. No trastuzumab-related effects on body weight, clinical signs, neurological function, clinical pathology, or anatomic pathology were noted. The applied doses and CSF concentrations achieved in the current study exceeded those reported in patients after intrathecal administration. The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in HER2-positive breast cancer.
authors.affiliation: Nonclinical Safety, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110-1199, USA. angelique.braen@roche.com
authors.forename: Angélique P J M
authors.initials: AP
authors.lastname: Braen
authors.forename: Josée
authors.initials: J
authors.lastname: Perron
authors.forename: Pierre
authors.initials: P
authors.lastname: Tellier
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Catala
authors.forename: Gerry
authors.initials: G
authors.lastname: Kolaitis
authors.forename: Wanping
authors.initials: W
authors.lastname: Geng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002408:Catheters, Indwelling; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D007263:Infusions, Parenteral; D008252:Macaca fascicularis; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D013131:Spine / Q000187:drug effects / Q000473:pathology; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab