Population Pharmacokinetics of Golimumab, an Anti‐Tumor Necrosis Factor‐α Human Monoclonal Antibody, in Patients With Psoriatic Arthritis

Abstract

The population pharmacokinetics of subcutaneously administered golimumab (50 mg or 100 mg every 4 weeks) were characterized in patients with active psoriatic arthritis (PsA) in GO-REVEAL, a randomized, double-blind, placebo-controlled, phase 3 study. A total of 2029 serum golimumab concentrations from 337 patients were analyzed using NONMEM. A 1-compartment pharmacokinetic model with first-order absorption and elimination was chosen to describe the observed concentration-time data. For a patient of standard weight (70 kg), the population estimates (typical value +/- standard error) for golimumab pharmacokinetic parameters were as follows: apparent clearance = 1.38 +/- 0.04 L/d, apparent volume of distribution = 24.9 +/- 1.04 L, and absorption rate constant = 0.908 +/- 0.121 per day. The between-subject variability was 37.6% in apparent clearance and 37.9% in apparent volume of distribution. Body weight, antibody-to-golimumab status, baseline C-reactive protein level, and smoking status were identified as significant covariates on apparent clearance. Body weight was also a significant covariate on apparent volume of distribution. None of the concomitant medications examined (methotrexate, corticosteroids, and nonsteroidal anti-inflammatory drugs) were significant covariates on apparent clearance, although the median trough golimumab concentration in patients receiving methotrexate was higher than for those not receiving methotrexate. These significant covariates account for part of the variability in systemic exposure to golimumab observed in patients with PsA.

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…Many of the therapeutic antibodies raised against soluble antigens such as circulating TNF, vascular endothelial growth factor (VEGF), IgE, and various cytokines (e.g., interleukin (IL)-8, IL-5, IL-12/IL-23) have undergone extensive research in both various animal models and clinical studies in patients (13,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). For this class of compounds, application of PK-PD modeling approaches can prove highly effective for the design of successful translational strategies (4,5,9,10).…”

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients

“…However, only body weight was found to be a significant covariant on apparent volume of distribution. In addition, golimumab concentrations in patients (50 mg golimumab every 4 weeks) not receiving MTX were 30% lower as compared with patients receiving MTX (Xu et al, 2009). So far, no possible explanation for the different effects of MTX on the serum golimumab concentrations has been provided (Xu et al, 2009).…”

“…Golimumab is a human immunoglobulin G1K Moab binding both soluble and transmembrane forms of TNF-, thereby neutralizing their bioactivity by blocking the interaction with receptor Xu et al, 2009).…”

“…In a study with 337 patients, the pharmacokinetics of subcutaneously administered golimumab (50 or 100 mg every 4 weeks) were analyzed (Xu et al, 2009) and the following golimumab pharmacokinetic parameters were found: apparent clearance = 1.38 ± 0.04 L per day, apparent volume of distribution = 24.9 ± 1.04 L and absorption rate constant = 0.908 ± 0.121 per day. Significant covariants on apparent clearance were identified as body weight, baseline C-reactive protein level and smoking habits.…”

Effects of Smoking on Immunologic and Skeletal Mechanisms Involved in Rheumatoid Arthritis and Responses of Various Biologic Therapies for RA

“…Differences in binding affinities between the three TNF inhibitors do not appear to account for differential response rates in smokers: the binding affinity of etanercept (Kd=0.4 pM) to TNFα was 10-20 fold greater than the affinity of infliximab (4.2 pM) or adalimumab (8.6 pM), yet adalimumab shows similar efficacy in RA patients who are smokers as etanercept [85]. Another possible mechanism is the effect of smoking on apparent clearance of the TNF blockers [89] which can be addressed in future studies.…”