Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with Ankylosing spondylitis.
OBJECTIVE
To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS).


METHODS
Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method.


RESULTS
The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively.


CONCLUSIONS
Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.
Fang
Yi
Y
Marine Drug and Food Institute, Ocean University of China, Qingdao, China.
Li
Lu-jin
LJ
Wang
Rui
R
Huang
Feng
F
Song
Hai-feng
HF
Tang
Zhong-ming
ZM
Li
Yu-zhen
YZ
Guan
Hua-shi
HS
Zheng
Qing-shan
QS
D000042:Absorption; D000328:Adult; D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics*; D002681:China; D004305:Dose-Response Relationship, Drug; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007279:Injections, Subcutaneous; D008297:Male; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013167:Spondylitis, Ankylosing / Q000097:blood / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult
D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D000068800:Etanercept