title: Pharmacokinetics, pharmacodynamics, and tolerability of single ascending doses of RCT-18 in Chinese patients with rheumatoid arthritis.
abstract: OBJECTIVE
  RCT-18 is a novel recombinant fusion protein that targets and neutralizes B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). This first in-human study investigated the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of RCT-18 in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  This was a single-center, randomized, single-blind, placebo-controlled study in 28 RA patients. Eligible patients were randomized 3:1 to receive single subcutaneous doses of RCT-18 (1.2, 6, 18, 60, 180, 360, 540 mg) or placebo. A 71-day observation period was scheduled for each patient, during which serial blood sampling for pharmacokinetic, pharmacodynamic, and immunogenicity assessments was performed. Safety was assessed throughout the study.
  
  
  RESULTS
  RCT-18 was well tolerated, although mild infections and skin irritation occurred more frequently in patients receiving this drug. After single-dose RCT-18, the maximal serum concentration (C max) of total and free RCT-18 was reached within 1-2 days, followed by a multi-exponential decline. Mean elimination half-life for total RCT-18 and free RCT-18 was 5.7-12.8 days and 3.2-11.3 days at 6-60 mg, and 15.1-17.5 days and 18.8-36.8 days with 180-540 mg RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to C max of 5-29 days and the elimination half-life mounting from 13.3 to 32.8 days with dose escalation. No positive reaction was detected in the immunogenicity assessments. Substantial IgM reduction was only evidenced with 540 mg RCT-18, while the response profiles of IgM/IgG were distinguishable from placebo after 180, 360, or 540 mg RCT-18.
  
  
  CONCLUSIONS
  RCT-18 was safe and well tolerated up to 540-mg single doses. The serum exposure of total and free RCT-18 is linearly correlated to the weight-normalized doses of RCT-18 in dose groups receiving 180-540 mg RCT-18. The elimination half-life of BLyS-RCT-18 increased with RCT-18 doses, suggesting a shift from target-mediated disposition in 1.2-18 mg RCT-18 groups to non-specific clearance in 60-540 mg RCT-18 groups. Assuming the concentration of BLyS-RCT-18 complex and the IgM/IgG ratio are surrogate biomarkers for clinical effects of RCT-18, the dose-response relationship suggests 180-540 mg are pharmacodynamically effective doses in RCT-18 for RA patients, but the effect profile of 540 mg RCT-18 on IgM is similar to that of atacicept at pharmacodynamically effective but clinically ineffective doses.
authors.affiliation: Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, 41 Damucang Alley, Xicheng District, Beijing, 100032, China, chenxia@pumch.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Hou
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Wen
authors.initials: W
authors.lastname: Zhong
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Wang
authors.forename: Xuejing
authors.initials: X
authors.lastname: Yao
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fang
authors.forename: Fengchun
authors.initials: F
authors.lastname: Zhang
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D001835:Body Weight; D002681:China; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D016037:Single-Blind Method; D053303:Transmembrane Activator and CAML Interactor Protein / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C000599360:RCT-18 fusion protein; D011993:Recombinant Fusion Proteins; D053303:Transmembrane Activator and CAML Interactor Protein