Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with Ankylosing spondylitis

Abstract

Aim:To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFRFc) 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 rhTNFRFc. 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. Conclusion: 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.

Comparative Pharmacokinetics, Safety, and Immunogenicity Study of the Prefilled Syringe and Lyophilized Formulation of a Recombinant Human Tumor Necrosis Factor‐α Receptor II:lgG Fc Fusion Protein in Healthy Chinese Male Subjects

“…It is worth noting that sex significantly affected the PK profile of rhTNFR:Fc in the Chinese population, the apparent clearance of men was 0.665 times as high as that of women. 19 Similar results were also reported in the American population: The apparent clearance of men was higher than that of women in patients with RA, although this difference did not reach statistical significance. 20,21 Currently, whether the dosage of rhTNFR:Fc should be adjusted based on sex difference is unclear and should be investigated in larger trials.…”

A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins

“…However, a general trend for underprediction of t max was observed when using the PBPK model. Lag times of up to 3 h have been included in other models of TP SC absorption to describe the time delay between dose and recovery in central lymph (14,36,45,76–78). Similarly, the radiolabelled IgG data used for model development showed a lag of ~0.5 h between dosing and loss of IgG from the dose site (28–30).…”

Comparative Pharmacokinetics of HD203, a Biosimilar of Etanercept, with Marketed Etanercept (Enbrel®)

“…[11,[18][19][20][21] In addition, a previous population-based pharmacokinetic study of etanercept indicated that the pharmacokinetics in rheumatoid arthritis and ankylosing spondylitis patients is similar to that in healthy volunteers. [22][23][24] Therefore, reconstituted lyophilized (25 mg mL) HD203 and Enbrel Ò can be expected to result in similar pharmacokinetics in the clinical setting. However, due to the absence of pharmacodynamic markers for etanercept in healthy subjects, a comparative pharmacodynamic or efficacy trial of HD203 in a large number of patients will be required to demonstrate comparability.…”