Summary

• Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein).¹
• The mean terminal half-life was estimated to be 12±3 days in healthy subjects and the mean terminal half-life in rheumatoid arthritis (RA) patients was 14±4 days.¹
• To assess the intravenous (IV) golimumab pharmacokinetic (PK) profile, studies evaluated numerous drug characteristics, including half-life and bioavailability.^1-3

CLINICAL STUDIES

Pharmacokinetic Parameters: Absolute Bioavailability, Median Terminal Half-life

Zhou et al (2007)⁴ conducted a randomized, double-blind, placebo-controlled, parallel-group, first-in-human study to assess the pharmacokinetic (PK) profile and safety of golimumab following a single IV infusion in 36 patients with active RA.

Study Design/Methods

• Eligible patients were >18 years of age, had a diagnosis of RA per the American College of Rheumatology (ACR) criteria with an active disease duration of >3 months from the onset of persistent synovitis. Eligible patients were also required to have at least 8 tender and 6 swollen joints and elevated acute phase reactants (C-reactive protein [CRP] >20% the laboratory reference or erythrocyte sedimentation rate [ESR] ≥28 mm/hr).
• Patients were excluded if they had received anti-TNF agents in the past; however, patients could have been treated with ≤3 doses of infliximab, with the last dose administered no less than 4 months prior to study agent administration. Stable doses of up to 2 disease-modifying antirheumatic drugs (DMARDs), corticosteroids (prednisone equivalent ≤10 mg/day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) were permitted.
• Patients were randomized to 1 of the following single infusion treatment groups: golimumab 0.1 mg/kg (n=3), golimumab 0.3 mg/kg (n=3), golimumab 1 mg/kg (n=5), golimumab 3 mg/kg (n=5), golimumab 6 mg/kg (n=5), golimumab 10 mg/kg n=5), or placebo (n=10). Infusions were administered over a 2-hour period.
• Sera to measure golimumab concentrations were collected prior to administration, immediately following administration, and at 1, 4, 8, and 24 hours after the infusion. Additionally, sera were collected at day 3, and at weeks 1, 2, 4, 8, 12, and 16.
• The following parameters were determined by conducting a noncompartmental PK analysis: maximum serum concentration (C_max), terminal elimination rate constant (λ_z), area under the serum concentration-time curve from time 0 to infinity (AUC [0-t_z]), terminal elimination half-life (t_1/2), and total body clearance (CL).
• A traditional compartmental PK model was employed to evaluate CL, volume of distribution in the central compartment (V_c), intercompartmental clearance (Q), and volume of distribution in the peripheral compartment (V_p).
• PK data from 198 serum samples from 21 patients receiving golimumab were utilized to develop a base population PK model.
• A covariate model was developed to identify significant covariates on golimumab PK parameters.

Results

Patient Characteristics

• Among patients in the golimumab dose groups, the median age was 53 years and the median weight was 72.7 kg.
• Patients had active disease as indicated by the median swollen joint count (19), tender joint count (n=25), and patient and evaluator global assessment of disease activity (5.4 and 6.4, respectively, on a 10-cm visual-analog scale).

PK Parameters

• PK parameters estimated derived from the noncompartmental analysis are shown in Table: Summary of PK Parameters Based on Noncompartmental Analysis. A dose-proportional increase in t_1/2 and C_max was observed. An independent relationship was noted between the CL of golimumab and the golimumab dose at a range of 0.1 to 10 mg/kg.
• Based on a 2-compartment linear model with constant infusion input and first-order elimination, the estimates for CL, V_c, and V_p were 0.44 L/d, 3.16 L, and 4.31 L, respectively.
• Based on a 2-compartment model with first-order elimination and zero-order input, the population PK parameter estimates for CL, V_c, V_p, and Q were 0.40 L/d, 3.23 L, 3.68 L, and 0.42 L/d, respectively.
• Body weight was noted to be a significant covariate on V_c.

Xu et al (2010)⁵ conducted a randomized, open-label, parallel-group, phase 1 study to determine the absolute bioavailability of golimumab when administered into 3 sites of the body (upper arm, abdomen, or thigh) by evaluating the PK profile following a single IV or subcutaneous (SC) injection of 100 mg in 78 healthy male individuals.

Study Design/Methods

• Individuals eligible for the study were healthy males aged 18 to 50, with a body weight of 60 to 90 kg and a body mass index (BMI) of 23 to 30 kg/m².
• Individuals were randomized in a 1.2:1:1:1 ratio to receive golimumab 100 mg by either a 30-minute IV infusion or SC injection at 1 of 3 sites of the body (upper arm, abdomen, or thigh).
• Serum samples were collected 1 hour before and 8 hours following golimumab administration, as well as on days 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, and 71. Additionally, for individuals randomized to receive IV golimumab, serum samples were also collected 1 hour after completion of the infusion. Standard noncompartmental methods were used to determine PK parameters.

Results

• Of the 78 patients originally randomized, 76 were included in the PK analysis (22 patients in the IV group and 18 patients in each of the 3 SC groups).
• The groups were well matched with respect to demographics at baseline. The mean age was 31.0 years (range: 18–50) with mean weight of 79.1 kg (63.0–90.0) and mean BMI of 25.7 kg/m² (range: 22–30).
• As shown in the Table: Summary of PK Parameters Following a Single Dose of Golimumab 100 mg by Either IV or SC Administration, the overall mean absolute bioavailability of golimumab administered SC was 51.1%. Further, the mean bioavailability was similar for the 3 different SC injection sites.
• The median t_1/2 was similar following SC (10.9) and IV administration (11.8 days).
• The mean CL and volume of distribution (during the terminal phase) following IV administration were 6.9 mL/kg/day and 115.1 mL/kg, respectively. Following SC administration, the mean body-weight adjusted apparent clearance for SC administration (CL/F) and apparent volume of distribution (during the terminal phase) were 13.8 mL/kg/day and 219.1 mL/kg, respectively.
• Other PK parameters for each treatment group are also summarized in Table: Summary of PK Parameters Following a Single Dose of Golimumab 100 mg by Either IV or SC Administration.
• Among the 74 patients with appropriate serum samples, 1 patient (1.4%) was positive for antibodies to golimumab with a low titer of 1:10.

Zhuang et al (2012)⁶ evaluated the PK profile of golimumab following multiple IV or SC injections in patients with RA in an open-label randomized, phase 1 study. Additionally, post hoc analyses were conducted to evaluate the impact of concomitant MTX therapy and baseline CRP on golimumab PK following repeated SC injections.

Study Design/Methods

• A total of 51 patients (49 patients received treatment) with active RA (≥4 tender and swollen joints, plus at least 2 of the following: 1) CRP ≥1.5 mg/dL or ESR ≥28 mm/hr, 2) morning stiffness ≥30 minutes, or 3) rheumatoid factor [RF] or anti-cyclic citrullinated peptide [CCP] positivity) were randomized in a 2:1 ratio to receive golimumab 100 mg SC every 4 weeks (n=33, 6 doses) or golimumab 2 mg/kg IV every 12 weeks (n=16, 2 doses).
• The protocol allowed for concomitant use of ≤3 DMARDs if doses were stable for ≥3 months prior to screening. Also, concomitant MTX therapy was permitted at a maximum dose of 25 mg/week. Stable doses of NSAIDs or other analgesics for RA and oral corticosteroids were also allowed.
• Exclusion criteria included use of etanercept or anakinra (within 1 month) or infliximab, golimumab, adalimumab, or abatacept (within 3 months) prior to first administration of study agent.
• Serial serum samples were collected and analyzed for golimumab concentrations using a validated electrochemiluminescent bioassay. Baseline CRP levels were also measured.
• A non-compartmental approach was utilized to determine the PK profile of golimumab.
• Subgroups were categorized based on a CRP cutoff of 1.0 mg/dL.

Results

• At baseline, the groups were well balanced regarding demographics and baseline characteristics. The mean age ranged from 55 to 57 years and most patients were female (~75%). The mean baseline CRP levels ranged from 0.8 to 1.2 mg/dL and 16 patients (11 in the SC group and 5 in the IV group) had baseline CRP levels that were ≥1 mg/dL.
• As shown in Table: Summary of PK Parameters Following Multiple Doses of Golimumab by IV or SC Administration, the mean (standard deviation) t_1/2 was 13.2 (2.9) days in the golimumab IV group and 13.1 (5.0) days in the golimumab SC group.
• Serum golimumab concentrations reached steady-state by ~12 weeks following SC administration. The mean trough golimumab concentrations ranged from 1.15 to 1.24 µg/mL at steady-state.
• The mean absolute bioavailability was estimated to be 53% for patients receiving golimumab SC.

• Mean serum golimumab concentrations were generally higher among patients treated with concomitant MTX. The mean t_1/2 was 14.7 and 11.0 days in patients who did and did not receive concomitant MTX, respectively.
• The geometric mean CL/F was 13.9 mL/day/kg in patients receiving concomitant MTX and 21.2 mL/day/kg in patients not receiving concomitant MTX.
• Among MTX-naive patients receiving golimumab SC, serum golimumab concentrations were generally lower in patients with elevated CRP (≥1 mg/dL; mean C_max after first dose: 3.1 µg/mL) vs. those with normal CRP (<1 mg/dL; mean C_max after first dose: 6.2 µg/mL). The mean golimumab CL/F was 29.7 and 15.8 mL/day/kg in patients with elevated CRP and normal CRP, respectively.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 May 2024.

Summarized in this response are relevant data from PK studies.