Yanli Zhuang

Subcutaneous Bioavailability of Golimumab at 3 Different Injection Sites in Healthy Subjects

This study characterized the pharmacokinetics (PK) of golimumab, an antitumor necrosis factor alpha human IgG1k monoclonal antibody, after a single intravenous (IV) or subcutaneous (SC) administration in healthy subjects and determined the absolute bioavailability of SC golimumab delivered at 3 different anatomical regions. Seventy‐eight healthy adult males were randomly assigned to receive a single dose of golimumab 100 mg by IV (30‐minute infusion, n = 23) or SC administration at different sites (upper arm, n = 18; abdomen, n = 18; thigh, n = 19). Serial blood samples were collected for PK characterization. Following IV administration, the mean maximum observed serum golimumab concentration (Cmax) and the mean area under the concentration versus time curves from time zero to infinity (AUC0‐∞) were 29.5 ± 5.8 μg/mL and 195.9 ± 48.9 μg·d/mL, respectively. After SC administration, the mean values of Cmax and AUC0‐∞ were 6.3 ± 2.8 μg/mL and 100.1 ± 29.2 μg·d/mL, respectively. The median terminal half‐life was similar for SC and IV administration (10.9 and 11.8 days, respectively). The overall mean bioavailability of SC golimumab was 51%, and absorption was similar for the 3 injection sites. Golimumab 100 mg was generally well tolerated in this study. Results support the flexibility in the choice of an injection site for SC administration of golimumab.

Golimumab Pharmacokinetics After Repeated Subcutaneous and Intravenous Administrations in Patients with Rheumatoid Arthritis and the Effect of Concomitant Methotrexate: An Open-Label, Randomized Study

BACKGROUND The pharmacokinetics of golimumab, a human monoclonal antibody that inhibits the activity of tumor necrosis factor α, after a single subcutaneous (SC) or intravenous (IV) administration have been previously studied. OBJECTIVES The purpose of this study was to assess the pharmacokinetics of golimumab after multiple SC or IV administrations in patients with active rheumatoid arthritis (RA). The effect of concomitant methotrexate (MTX) use on golimumab pharmacokinetics was evaluated. METHODS In this open-label, randomized, Phase I study, 49 adult patients with RA received SC golimumab 100 mg (n = 33) every 4 weeks through week 20 or IV golimumab 2 mg/kg (n = 16) at weeks 0 and 12. Serial blood samples were collected, and serum golimumab concentration was measured with an electrochemiluminescent immunoassay. Golimumab pharmacokinetic parameters were derived with the use of a noncompartmental analysis. Adverse events were monitored at every visit. RESULTS The population was predominantly Caucasian (84%) and female (76%), and the median age was 57 years. After SC golimumab administration, the serum golimumab concentration achieved steady state by ∼12 weeks with mean trough serum concentrations ranging from 1.15 to 1.24 μg/mL. After the final 30-minute IV infusion of golimumab 2 mg/kg, the mean (SD) clearance (CL) was 7.5 (2.6) mL/d/kg. The mean terminal half-life after SC and IV administrations was ∼13 days. The mean absolute bioavailability for SC golimumab was estimated to be 53%. The geometric mean of golimumab CL/F in patients with and without concomitant MTX use was 13.9 and 21.2 mL/d/kg, respectively, and the geometric mean ratio of CL/F was 65.5% (90% CI: 45.2%-94.9%, P = 0.06). Golimumab was generally well tolerated. No malignancies or deaths occurred during the study. CONCLUSIONS Pharmacokinetics of golimumab were consistent after SC or IV administration in this population of patients with RA. Golimumab was well tolerated and no unexpected adverse events were observed in this trial.

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.

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.

Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

Disease-mediated therapeutic protein–drug interactions have recently gained attention from regulatory agencies and pharmaceutical industries in the development of new biological products. In this study, we developed a physiologically based pharmacokinetic (PBPK) model using SimCYP to predict the impact of elevated interleukin-6 (IL-6) levels on cytochrome P450 (CYP) enzymes and the treatment effect of an anti-IL-6 monoclonal antibody, sirukumab, in patients with rheumatoid arthritis (RA). A virtual RA patient population was first constructed by incorporating the impact of systemic IL-6 level on hepatic and intestinal expression of multiple CYP enzymes with information from in vitro studies. Then, a PBPK model for CYP enzyme substrates was developed for healthy adult subjects. After incorporating the virtual RA patient population, the PBPK model was applied to quantitatively predict pharmacokinetics of multiple CYP substrates in RA patients before and after sirukumab treatment from a clinical cocktail drug interaction study. The results suggested that, compared with observed clinical data, changes in systemic exposure to multiple CYP substrates by anti-IL-6 treatment in virtual RA patients have been reasonably captured by the PBPK model, as manifested by modulations in area under plasma concentration versus time curves for midazolam, omeprazole, S-warfarin, and caffeine. This PBPK model reasonably captured the modulation effect of IL-6 and sirukumab on activity of CYP3A, CYP2C9, CYP2C19, and CYP1A2 and holds the potential to be utilized to assess the modulation effect of sirukumab on the metabolism and pharmacokinetics of concomitant small-molecule drugs in RA patients.

Absolute Bioavailability and Pharmacokinetic Comparability of Sirukumab Following Subcutaneous Administration by a Prefilled Syringe or an Autoinjector

This phase 1, randomized, open‐label study assessed the absolute bioavailability and pharmacokinetic comparability of sirukumab, a human anti–interleukin‐6 monoclonal antibody, following subcutaneous (SC) administration via Prefilled Syringe‐UltraSafe Passive® Delivery System (PFS‐U) or Prefilled Syringe‐SmartJect® Autoinjector (PFS‐AI; Janssen Research & Development, LLC, Spring House, Pennsylvania). A total of 144 healthy male subjects were randomized to 5 single‐dose treatment groups: sirukumab 50 mg and 100 mg (each by PFS‐U and PFS‐AI) and sirukumab 100 mg intravenous (IV) infusion. Pharmacokinetic parameters were calculated using noncompartmental analysis. Following SC administration, maximum serum concentrations (Cmax) and area under the concentration‐vs‐time curve (AUC) increased in an approximately dose‐proportional manner. Median time to reach Cmax was 5 days, and mean half‐life ranged from 16 to 19 days. Mean absolute bioavailability of sirukumab by PFS‐AI and PFS‐U, respectively, was estimated at 92.4% and 81.4% with 100 mg and 88.4% and 94.7% with 50 mg. Ratios of geometric means (90% confidence intervals) of Cmax and AUC0‐77d for PFS‐AI:PFS‐U were 1.13 (1.03, 1.25) and 1.14 (1.05, 1.24), respectively, indicating comparable systemic exposures of sirukumab following a single 100‐mg SC dose by PFS‐U or PFS‐AI. The incidence of antibodies to sirukumab was low (1.4%). No new safety concerns associated with sirukumab were identified at either dose.

Exposure‐Response Modeling Analyses for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin 6, in Patients With Moderately to Severely Active Rheumatoid Arthritis

To characterize the dose‐exposure–response relationship of sirukumab, an anti–interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure‐response (E‐R) modeling analyses based on data from two pivotal phase 3 placebo‐controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease‐modifying antirheumatic drugs or anti‐tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28‐joint Disease Activity Index Score (DAS28) using C‐reactive protein. To provide a thorough assessment of the sirukumab E‐R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near‐maximal efficacy. No covariates identified in the E‐R modeling analyses would have a significant impact on dose‐response. Despite body weight and comorbid diabetes having significant effect on sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of sirukumab E‐R to support dose recommendations in patients with RA.

Confirmatory Population Pharmacokinetic Analysis for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin‐6, in Patients With Moderately to Severely Active Rheumatoid Arthritis

The population pharmacokinetics of sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin‐6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND‐D, ‐T, ‐H, and ‐M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1‐compartment linear model with first‐order absorption and first‐order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes <10%. The estimated apparent clearance (CL/F) and volume of distribution were 0.641 L/day and 16.1 L, respectively, at standard body weights of 70 kg. The terminal elimination half‐life was approximately 17.4 days. Sirukumab CL/F and volume of distribution increased with body weight, and CL/F was higher in patients with diabetic comorbidity. Simulations suggest that the effects of diabetic comorbidity and weight on sirukumab exposure were additive. To fully understand the clinical relevance including potential dose adjustment, current covariate findings need to be evaluated concurrently with the efficacy and safety data.

Risk-Based Comparability Assessment for Monoclonal Antibodies During Drug Development: A Clinical Pharmacology Perspective

Due to complexities in the structure, function, and manufacturing process of antibody-based therapeutic proteins, comparability assessment for supporting manufacturing changes can sometimes be a challenging task. Regulatory guidance recommends a hierarchical risk-based approach, starting with Chemistry, Manufacturing, and Controls (CMC) analytical characterizations, followed by non-clinical and/or clinical studies to ensure that any potential changes in quality attributes have no adverse impact on efficacy and safety of the product. This review focuses on the changes in quality attributes which may potentially affect the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of a monoclonal antibody (mAb) product, and provides general guidelines in designing non-clinical and clinical PK/PD studies to help support comparability assessments. A decision tree for comparability assessment is proposed depending on the nature of the changes in quality attributes, the potential impact of such changes, and the timing of the manufacturing change relative to the development process. Ideally, the optimization of manufacturing process should take place in the early stage of drug development (i.e., preclinical to phase 2a) as more stringent comparability criteria would have to be met if manufacturing changes occur in the late stage of drug development (i.e., phase 2b and after), and consequently, major changes in manufacturing process should be avoided during confirmatory phase 3 studies and post-approval of drug products.