title: In vivo pharmacokinetic and pharmacodynamic evaluation of the malononitrilamide FK778 in non-human primates.
abstract: The malononitrilamide FK778 is a leflunomide analogue with a shorter half-life than leflunomide. Groups of cynomolgus monkeys were treated orally with various doses of FK778 once daily for 7 days: group A, 10 mg/kg ( n=4); group B, 5 mg/kg ( n=3); and group C, one single loading dose of 20 mg/kg followed by 5 mg/kg once daily ( n=2). Trough plasma concentration of FK778 was measured by HPLC. Lymphocyte proliferation and expression of T-cell activation surface antigens were assessed by flow cytometry. In group A, trough plasma concentration of FK778 reached steady state at 48 h. After 7 days, lymphocyte proliferation was 23+/-7.4% (mean +/- SEM) and expression of CD71, CD25, CD11a and CD95 on T cells was less than 50% of pre-treatment baseline values. In group B, trough plasma levels of FK778 did not reach steady state, but dropped to near-zero levels after 3 days and on day 7 and lymphocyte proliferation and T-cell surface antigen expression were not different from pre-treatment baseline values. In group C, FK778 trough levels did not reach steady state, but drug exposure was evident over the entire period of treatment, and on day 7, lymphocyte proliferation was 11.4+/-8.6% of pre-treatment baseline values. We conclude that FK778 inhibits lymphocyte proliferation and expression of T-cell activation antigens in vivo in non-human primates after 1 week of treatment. These effects are related to the total drug exposure over the time of treatment. At doses lower than 10 mg/kg daily, FK778 is cleared from the circulation between the dosing intervals, thus failing to exert its inhibitory effects on immune functions.
authors.affiliation: Transplantation Immunology Laboratory, Falk CVRB, 300 Pasteur Drive, Stanford, CA 94305-5407, USA.
authors.forename: Tudor
authors.initials: T
authors.lastname: Bîrsan
authors.forename: Camille
authors.initials: C
authors.lastname: Dambrin
authors.forename: Jochen
authors.initials: J
authors.lastname: Klupp
authors.forename: Mario
authors.initials: M
authors.lastname: Stalder
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Larson
authors.forename: William E
authors.initials: WE
authors.lastname: Fitzsimmons
authors.forename: Randall E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000480:Alkynes; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics*; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D009570:Nitriles; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide