First-in-human study to assess guselkumab (anti-IL-23 mAb) pharmacokinetics/safety in healthy subjects and patients with moderate-to-severe psoriasis.

PURPOSE: The purpose of this study is to evaluate the pharmacokinetics, immunogenicity, safety, and tolerability of guselkumab, a human monoclonal antibody with high affinity and specificity for binding to interleukin-23. METHODS: In this first-in-human, phase 1, randomized study, a single intravenous (IV; 0.03-10 mg/kg) or subcutaneous (SC; 10-300 mg) dose of guselkumab was administered to 47 healthy subjects, and a single SC dose (placebo, 10, 30, 100, 300 mg) was administered to 24 patients with moderate-to-severe psoriasis. RESULTS: Mean maximum observed serum concentration and area under the zero-to-infinity serum concentration-time curve of guselkumab increased in an approximately dose-proportional manner over the dose range of 0.03-10 mg/kg following a single IV administration or 10-300 mg following a single SC administration. Mean clearance and volume of distribution ranged from 3.62-6.03 mL/day/kg and 99.38-123.22 mL/kg, respectively. Mean half-life ranged from 12 to 19 days in healthy subjects and patients with psoriasis. Among guselkumab-treated subjects/patients, 1/30 (3.3 %) healthy subjects in the IV group, 0/6 healthy subjects in the SC group, and 1/20 (5.0 %) patients with psoriasis tested positive for antibodies to guselkumab. No clinically significant adverse events were identified in this study. CONCLUSION: Guselkumab pharmacokinetic profiles were generally comparable between healthy subjects and patients with psoriasis. Guselkumab, administered as an IV infusion or SC injection, was well tolerated in healthy subjects and patients with psoriasis.

Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis.

BACKGROUND: IL-23 expression is increased in psoriatic lesions and might regulate TH17 T-cell counts in patients with psoriasis. OBJECTIVES: We sought to test a novel IL-23-specific therapeutic agent for the treatment of psoriasis. METHODS: In this randomized, double-blind, placebo-controlled study the safety, tolerability, and clinical response of guselkumab, an anti-IL-23-specific mAb, were evaluated in patients with moderate-to-severe plaque psoriasis. A total of 24 patients were randomized to receive a single dose of placebo or 10, 30, 100, or 300 mg of guselkumab. Clinical response was assessed by using the Psoriasis Area and Severity Index (PASI). Additionally, histologic analysis and gene expression in skin biopsy specimens from guselkumab-treated patients were compared with those from placebo-treated patients. RESULTS: At week 12, 50% (10 mg), 60% (30 and 100 mg), and 100% (300 mg) of guselkumab-treated patients, respectively, achieved a 75% improvement in PASI scores from baseline compared with 0% of placebo-treated patients. Improvements in PASI scores were generally maintained through week 24 in all guselkumab-treated patients. The proportion of patients experiencing an adverse event was comparable between the combined guselkumab (13/20 [65.0%]) and placebo (2/4 [50.0%]) groups through week 24. Analysis of lesional and nonlesional skin biopsy specimens demonstrated decreases in epidermal thickness and T-cell and dendritic cell expression in guselkumab-treated patients compared with values seen in placebo-treated patients. At week 12, significant reductions in psoriasis gene expression and serum IL-17A levels were observed in guselkumab-treated patients. CONCLUSION: IL-23 inhibition with a single dose of guselkumab results in clinical responses in patients with moderate-to-severe psoriasis, suggesting that neutralization of IL-23 alone is a promising therapy for psoriasis.

Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis.

Golimumab is a fully human antitumor necrosis factor alpha (TNF-alpha) monoclonal antibody that is being developed for intravenous and subcutaneous administration. To assess the pharmacokinetics and safety of the intravenous formulation of golimumab, 36 adult subjects with rheumatoid arthritis were randomly assigned to receive a single infusion of placebo or golimumab (0.1, 0.3, 1, 3, 6, or 10 mg/kg). Serum concentrations of golimumab were determined using a validated enzyme-linked immunosorbent assay method. In addition to the noncompartmental analysis and compartmental modeling, a population pharmacokinetics analysis using NONMEM was also conducted. Both the maximum serum concentration and the area under the serum concentrationtime curve appeared to increase in a dose-proportional manner. The median half-life ranged from 7 to 20 days. A 2-compartment population pharmacokinetic model adequately described the pharmacokinetics of golimumab. The following pharmacokinetic parameters (typical value [% coefficient of variation]) were estimated from the population pharmacokinetic model: clearance (CL: 0.40 [10.1%] L/d), volume of distribution in the central compartment (V(c): 3.07 [6.4%] L), intercompartmental clearance (Q: 0.42 [15.5%] L/d), and volume of distribution in the peripheral compartment (V(p): 3.68 [11.8%] L). Interindividual variability of the pharmacokinetic parameters was quantified for CL (44.3%), V(c) (25.5%), Q (44.6%), and V(p) (44.6%). Residual variability was estimated to be 15.0%. Body weight was found to be an important covariate on V(c). Golimumab was generally well tolerated. The pharmacokinetics of golimumab appeared to be linear over the dose range evaluated in this study.

Pharmacokinetic bridging approach for developing biologics-delivery devices: a case study with a golimumab autoinjector.

PURPOSE: This Phase 1 pharmacokinetic (PK) comparability study in healthy subjects was performed to compare the PK properties and tolerability of single-dose golimumab 100 mg delivered subcutaneously by an autoinjector device or by a standard needle and syringe that had been used for the subcutaneous (SC) delivery of golimumab in pivotal Phase 3 studies. METHODS: Healthy male subjects were randomly assigned to receive a single injection of SC golimumab 100 mg using either the autoinjector or a standard needle and syringe. The PK parameters of golimumab were calculated using noncompartmental analysis. An ANOVA model was applied to compare the 2 injection methods with regard to golimumab C(max) and the AUC from 0 and 49 days after administration (AUC(0-49d)). FINDINGS: In the prespecified evaluable PK population (n = 141), the mean (SD) values for C(max) were 6.6 (3.3) and 6.0 (3.0) µg/mL, and AUC(0-49d) values were 97.4 (43.2) and 88.9 (36.8) µg·d/mL in the autoinjector and needle/syringe groups, respectively. The 90% CI of the geometric mean ratios of the AUC(0-49d) values between the 2 delivery methods was 95.17% to 120.55%; the 90% CI of the geometric mean ratio of C(max) was 96.14% to 127.42%. In a post hoc intent-to-treat analysis using data from all 156 subjects, the 90% CIs of both C(max) and AUC(0-49d) fell within the prespecified range for bioequivalence (80% to 125%). The prevalences of adverse events were similar between the 2 groups. IMPLICATIONS: The totality of the study findings suggests that the PK properties and tolerability of SC administration of golimumab by the 2 delivery methods were comparable. The study results successfully bridged the container-closure change from a liquid-in-vial product to either a prefilled syringe or an autoinjector with the same liquid formulation.

Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-interleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach.

This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) ≥ 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.03 mg/kg midazolam, 10 mg warfarin + 10 mg vitamin K (equivalent to 5 mg S-warfarin), 20 mg omeprazole, and 100 mg caffeine 1 week before and 1, 3, and 6 weeks after a single subcutaneous dose of 300 mg sirukumab. The results showed that the pharmacokinetics of midazolam, omeprazole, and S-warfarin were nonequivalent before and after the administration of a single dose of 300 mg sirukumab. Area under the plasma concentration-time curve (AUC0- ∞ ) for midazolam, omeprazole, and S-warfarin was reduced by 30%-35%, 37%-45%, and 18%-19%, respectively, after sirukumab administration. Caffeine AUC0-∞ was increased by 20%-34% after sirukumab administration. The effect of sirukumab on CYP substrates was sustained for at least 6 weeks. No new adverse drug reactions related to the administration of sirukumab were observed in this study. These results suggest that sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active RA.

Reduced inhibition by abciximab in platelets with the PlA2 polymorphism.

BACKGROUND: The PlA2 polymorphism of the glycoprotein IIb/IIIa (fibrinogen) receptor has been associated with increased restenosis and stent thrombosis. We postulated that this allele could alter the antiplatelet effect of abciximab in patients undergoing percutaneous coronary intervention. METHODS: Optical platelet aggregation assays, Ultegra (Accumetrics, San Diego) rapid platelet function assays, and radiometric abciximab binding assays were performed in 66 Pl(A1/A1) and 21 PlA1/A2 patients undergoing percutaneous coronary interventions. The affinity of abciximab for the PlA1 and PlA2 receptors was determined with use of transfected cells. RESULTS: Compared with PlA1/A1 homozygotes, PlA1/A2 platelets were less completely inhibited after abciximab bolus (P =.002) and at 24 hours (P =.02) as assessed by the rapid platelet function assays. Optical aggregation assays confirmed that Pl(A1/A2) platelets were less completely inhibited after abciximab bolus (P =.05). The radiometric abciximab binding assay demonstrated that the PlA1/A2 platelets had fewer baseline fibrinogen receptors than did the PlA1/A1 platelets (P =.04) and more free fibrinogen receptors at 24 hours (P =.008). Cells transfected to express homozygous PlA1 or PlA2 demonstrated a nonsignificant trend (P =.12) for reduced abciximab affinity for PlA2. CONCLUSIONS: PlA1/A2 platelets are less completely inhibited with abciximab, contributing to the observed interindividual variability in platelet function inhibition. Because the extent of platelet inhibition is an independent predictor for the risk of major adverse coronary events after percutaneous coronary intervention, the relative resistance of PlA2-positive platelets may contribute to a less favorable outcome in these patients.

An additional mechanism of action of abciximab: dispersal of newly formed platelet aggregates.

BACKGROUND: The ability of abciximab to prevent fibrinogen binding to activated platelets indicates it may also promote dissolution of platelet-rich thrombi. The present study examined the capacity of abciximab to reverse platelet aggregation in vitro. METHODS AND RESULTS: Experiments were performed on blood from healthy non-medicated donors. Platelet aggregate formation and disaggregation were monitored turbidimetrically. Platelet-bound fibrinogen was measured by flow cytometry. For disaggregation studies, platelets were first stimulated with either ADP or the 11-mer thrombin receptor activating peptide (TRAP), then varying amounts of abciximab were added at periodic intervals after agonist addition. Platelet disaggregation was detected by comparing the extent of light transmittance at 4 min after addition of either abciximab or saline to PRP. ATP release was simultaneously monitored by chemi-luminescence. When added 1 min after low concentrations of ADP, abciximab rapidly (< 1 min) dispersed platelet aggregates in a dose-dependent manner, with complete disaggregation observed with 6.25 microg/mL of the beta3 antagonist. In contrast, equivalent concentrations of abciximab did not induce appreciable disaggregation to platelets stimulated with TRAP (10 microM). Platelet counts of samples that had undergone complete disaggregation, as assessed by aggregometry, were equivalent to baseline, indicating dispersal of aggregates to single cells. Concentrations of abciximab that produced complete disaggregation induced partial displacement of platelet-bound fibrinogen (52 +/- 8% inhibition of fibrinogen binding at 12.5 microg/ml abciximab). The disaggregation effectiveness of abciximab decreased as the time between ADP and subsequent abciximab addition widened, and as the amount of both dense granule release and agonist stimulation increased. However, pre-treatment of platelets with acetylsalicylic acid (ASA) did not potentiate platelet disaggregation induced by abciximab. CONCLUSIONS: These data indicate that abciximab facilitates the dispersal of newly formed platelet aggregates in vitro, by partially displacing fibrinogen from activated GPIIb/IIIa receptors. In vivo, abciximab may destabilize coronary thrombi by preventing aggregate formation and dispersing mural thrombi.