title: Tolerability of cyclosphosphamide and methotrexate induction immunosuppression in nonhuman primates.
abstract: Transplantation in nonhuman primates, in particular using solid organs from porcine donors, requires an efficacious induction immunosuppression. Besides biologicals, the low molecular weight drugs used include cyclophosphamide (CyP) and methotrexate (MTX). As these compounds generally have a narrow therapeutic window, we performed tolerability studies in baboons and cynomolgus monkeys, with/without maintenance immunosuppressants such as cyclosporine A, everolimus, mycophenolate sodium and FTY720. In both species, a four-dose CyP regimen of 40, 20, 30 and 30 mg/kg i.v. on days 1, 2, 4 and 6 is not tolerated, but the regimen is tolerated upon individual adjustment of the third and fourth dose to 18-25 and 8-20mg/kg, respectively, based on white blood cell count. In cynomolgus monkeys, a 5-day course of MTX i.v. at 0.5 mg/(kg d) is well tolerated, but not MTX at 1.0 mg/(kg d); in combination with maintenance immunosuppression, the 0.5mg/(kg d) dose can cause adverse effects. Combinations of CyP and MTX are tolerated using the 5-day course of MTX at 0.25 mg/(kg d) and a four-dose regimen of CyP at 10, 2.5, 7.5 and 7.5 mg/kg. These regimens are tolerated in combination with maintenance immunosuppressants. The data provide base values for investigators using nonhuman primates in experimental studies, particularly in xenotransplantation requiring effective induction immunosuppression that is close to maximum tolerated dose levels.
authors.affiliation: Imutran Ltd. (A Novartis Pharma AG Company), Cambridge CB2 2YP, UK. henkjan.schuurman@numico-research.nl
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Schuurman
authors.forename: Harold T
authors.initials: HT
authors.lastname: Smith
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cozzi
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology / Q000633:toxicity*; D016572:Cyclosporine / Q000494:pharmacology; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000633:toxicity*; D007958:Leukocyte Count; D008252:Macaca fascicularis; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity*; D009173:Mycophenolic Acid / Q000494:pharmacology; D016377:Organ Transplantation / Q000662:veterinary; D010215:Papio; D011409:Propylene Glycols / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D003520:Cyclophosphamide; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D009173:Mycophenolic Acid; D013110:Sphingosine; D020123:Sirolimus; D008727:Methotrexate