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Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevents the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double‐blind, placebo‐controlled trial in patients with moderately to severely active Crohn disease (CD). While the proof‐of‐concept part I of the study demonstrated significant treatment effects, part II (dose‐ranging) revealed an unexpected lack of dose‐response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure‐response (E‐R) analyses were planned and performed. A 1‐compartment PopPK model with first‐order absorption and parallel linear and nonlinear elimination pathways was established for tesnatilimab in patients with CD. No clinically significant covariates were identified, and overall consistent pharmacokinetics were observed between part I and part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood natural killer group 2 member D receptors and target engagement at all tested dose levels. Pooled part I and part II data showed a positive efficacy E‐R relationship; however, this was driven by data from part I. Part II–only analysis did not show an apparent efficacy E‐R relationship. No important covariates were identified in efficacy E‐R analyses, overall, and in various subpopulations. No apparent E‐R relationships were observed for the investigated safety end points. The PopPK and E‐R analyses indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement. [ABSTRACT FROM AUTHOR]

The main objective of this tutorial is to provide the readers with a roadmap of how to establish increasingly complex target‐mediated drug disposition (TMDD) models for monoclonal antibodies. To this end, we built mathematical models, each with a detailed visualization, starting from the basic TMDD model by Mager and Jusko to the well‐established, physiologically based model by Li et al. in a step‐wise fashion to highlight the relative importance of key physiological processes that impact mAb kinetics and system dynamics. As the models become more complex, the question of structural and parameter identifiability arises. To address this question, we work through a trastuzumab case example to guide the modeler's choice for model and parameter optimization in light of the context of use. We leave the readers of this tutorial with a brief summary of the advantages and limitations of each model expansion, as well as the model source codes for further self‐guided exploration and hands‐on analysis. [ABSTRACT FROM AUTHOR]

The purpose of this study is to characterize the population pharmacokinetics (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety end points in patients with newly diagnosed systemic amyloid light‐chain amyloidosis. The popPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run‐in, n = 28; randomized phase, n = 183). Nonlinear mixed‐effects modeling was used to characterize the popPK and quantify the impact of potential covariates. The exposure‐response (E‐R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy end points. The E‐R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration‐time data of daratumumab SC were well described by a 1‐compartment popPK model with first‐order absorption and parallel linear and nonlinear Michaelis‐Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety end points. In conclusion, the popPK and E‐R analyses supported the selected 1800‐mg flat dose of daratumumab SC in combination with the bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light‐chain amyloidosis. No dose adjustment was recommended for investigated covariates. [ABSTRACT FROM AUTHOR]

Guselkumab is an anti‐interleukin‐23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure‐response relationship of guselkumab in PsA, population PKs, and exposure‐response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration‐time data of guselkumab were adequately described by a one‐compartment linear PK model with first‐order absorption and elimination. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure‐response relationships were demonstrated with landmark and longitudinal exposure‐response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator's Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C‐reactive protein level were identified as influencing covariates on guselkumab exposure‐response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure‐response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA. [ABSTRACT FROM AUTHOR]

Ustekinumab (STELARA) is a human monoclonal antibody against interleukins‐12 and −23 for the treatment of adult and adolescent (≥ 12 to < 18 years of age) patients with moderate‐to‐severe plaque psoriasis. A phase III study was recently completed in pediatric patients (≥ 6 to < 12 years of age) with psoriasis. The objectives of the current analysis were to develop a population pharmacokinetic (PK) model and a joint longitudinal exposure‐response model using ordered categorial end points derived from Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores (namely a joint PASI response criteria (PRC) and PGA model) to characterize the PK and exposure‐response relationship of ustekinumab in pediatric patients with psoriasis. The developed pediatric models reasonably predicted the PK of ustekinumab, as well as the PRC and PGA clinical response in pediatric patients with psoriasis. In addition, the joint PRC and PGA modeling framework was able to adequately extrapolate clinical response in pediatric patients using data collected from clinical studies in adult patients with psoriasis. [ABSTRACT FROM AUTHOR]

The importance of pharmacokinetic (PK) evaluation in pediatric drug development is well recognized, and a pediatric PK study is generally recommended before pivotal trials to ensure the "right" dose in these studies. The PK of therapeutic monoclonal antibodies (mAbs) is primarily affected by body weight, where adults‐to‐children extrapolation may conform to allometry. Therefore, PK behavior of mAbs in pediatrics, particularly for those with linear PK, is expected to be predictable based on data in adults. To test this hypothesis, we reviewed published population PK reports of marketed mAbs and assessed model‐aided PK extrapolation of mAbs to children (2‐17 years) through 5 case studies. For each case study, population PK models were developed based on adult data, with allometric exponents of weight on clearance and volume of distribution fixed as standard values (ie, 0.75 for clearance; 1.0 for volume of distribution), approach 1, or coming from adult model estimates, approach 2. Simulated pediatric PK using these 2 approaches was compared with PK observations in pediatric trials to assess the accuracy in model predictions. For pediatrics 6‐17 years, model performance was generally comparable with the 2 approaches. For children < 6 years, no definite conclusion could be made, as only 1 case study enrolled children 2‐5 years. Our work supports that PK in children 6‐17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry). Empirical dosing calculations based on PK simulations with allometry are proposed to convert adult doses to equivalent pediatric doses with exposure matching for mAbs in children 2‐17 years. [ABSTRACT FROM AUTHOR]

To characterize the pharmacokinetics (PK) and exposure‐response (E‐R) relationship of ustekinumab, an anti‐interleukin‐12/interleukin‐23 (IL‐12/IL‐23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E‐R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration‐time data of ustekinumab were adequately described by a 2‐compartment linear PK model with first‐order absorption and first‐order elimination. Body weight, baseline serum albumin, sex, and antibodies to ustekinumab were the covariates to influence ustekinumab PK, but the magnitudes of the effects of these covariates were not considered clinically relevant, and dose adjustment was not warranted. Positive E‐R relationships were demonstrated between ustekinumab exposure metrics and clinical endpoints (including clinical response, clinical remission, and endoscopic healing based on Mayo score) at induction week 8 and maintenance week 44, consistent with the effectiveness of ustekinumab in the induction and maintenance treatment of patients with UC. E‐R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90‐mg subcutaneous every‐8‐week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90‐mg subcutaneous every‐12‐week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E‐R in a modeling framework to support ustekinumab dose recommendations in patients with UC. [ABSTRACT FROM AUTHOR]

Introduction: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers.Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications.Results: In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab.Conclusion: These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM.Trial Registration: ClinicalTrials.gov number, NCT01998971. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin‐G1‐lambda monoclonal antibody, binds to interleukin‐23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab‐treated patients across 3 phase 2/3 trials. Observed serum guselkumab concentrations were adequately described by a 1‐compartment linear PK model with first‐order absorption and elimination. The final PK model was robust and stable, with apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) estimates of 0.516 L/day, 13.5 L, and 1.11 day‐1, respectively. A model‐derived elimination half‐life of 18.1 days indicated achievement of steady‐state serum guselkumab concentrations within 12–14 weeks. The primary covariate contributing to the observed PK variability was body weight, which accounted for only 28% (CL/F) and 32% (V/F) of the interindividual proportion of variance. Diabetes was identified to marginally reduce guselkumab exposure, owing to 12% higher CL/F in diabetic versus nondiabetic patients, but its contribution was not clinically relevant. None of the other covariates tested (eg, age, sex, ethnicity, immune response to guselkumab, or concomitant medications) had a clinically relevant effect on guselkumab exposure. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM).Patients and Methods: Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies-GEN501 (N = 104) and SIRIUS (N = 124).Results: Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54-2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population.Conclusion: Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM. [ABSTRACT FROM AUTHOR]

Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005-24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM. Noncompartmental analysis was conducted to characterize daratumumab pharmacokinetics, and, in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells are eliminated. These and other pharmacokinetic data analyses support the use of the recommended dose regimen of daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to rapidly saturate target-mediated clearance during weekly dosing and maintain saturation when dosing every 2 or 4 weeks. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Study the disposition and target-neutralization capability of an anti-interleukin-6 (IL-6) monoclonal antibody (mAb) at the joint in a mouse collagen-induced arthritis (CIA) model. Methods: A mechanistic pharmacokinetic/pharmacodynamic study was conducted in a mouse CIA model using CNTO 345, a rat anti-mouse IL-6 mAb, as model compound. The drug, total/free IL-6 concentrations in both serum and joint lavage fluid were quantitatively assessed and compared to those in the normal control mice. Results: CNTO 345 exhibited higher clearance and significantly higher joint lavage/serum ratio in the CIA mice than in the normal control mice. The mAb concentrations in the joint lavage are approximately proportional to the serum concentrations at all the time points being examined. Dosing of CNTO 345 led to sustained free IL-6 suppression in both serum and joint lavage in a dose-dependent manner. A dose-dependent increase in total IL-6 was observed in serum, but not in the joint lavage fluid. Though no change in disease activity was observed following a single dose of anti-IL-6 mAb at peak of the disease, a dose-dependent decrease in serum amyloid A, a downstream biomarker of IL-6, was observed. Conclusions: This study provided quantitative assessments of the distribution and target-neutralization capability of an anti-IL-6 mAb at the site of action in an animal disease model. [ABSTRACT FROM AUTHOR]

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 5mg S-warfarin), 20mgomeprazole, and 100mg 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 300mg 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 sirukumabon 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. [ABSTRACT FROM AUTHOR]

Background and Objectives: Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1 monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated. Methods: This was a phase I, randomized, open-label, single-dose, single-period, single-center study. Twenty-four healthy male Chinese subjects were randomized (1:1) to receive a single SC administration of golimumab 50 or 100 mg. Serial blood samples for the measurement of serum golimumab concentrations were collected and analyzed using a validated electrochemiluminescent immunoassay method. The pharmacokinetic parameters [maximum observed serum concentration (C), time to reach C (t), area under the serum concentration-time curve from time zero to infinity (AUC), and terminal half-life (t)] of golimumab were derived using a noncompartmental analysis. Results: Following a single SC administration of golimumab 50 or 100 mg in Chinese male subjects (age 19-41 years, body weight 60-76 kg), mean ± standard deviation C (3.6 ± 1.6 and 7.5 ± 1.4 μg/mL, respectively) and AUC (59.8 ± 19.8 and 132.8 ± 27.0 μg·day/mL, respectively) increased in a dose-proportional manner. The median t was in the range of 4.5-5.0 days, and the mean t was in the range of 10.8-11.9 days. Among 24 subjects, 23 had appropriate samples for evaluation of antibodies to golimumab, and one subject (1/23, 4.3%) in the 100-mg group tested positive. Three mild adverse events were reported (infected sebaceous cyst, upper respiratory tract infection, and headache), all in the 50-mg group; none were considered to be related to the study agent. Conclusions: Golimumab exhibited linear pharmacokinetics at dose levels of 50 and 100 mg following a single SC administration in healthy Chinese subjects. Single SC administrations of golimumab 50 or 100 mg were considered to be generally well tolerated. The results from this study indicate that there are no apparent ethnic differences in the pharmacokinetics of golimumab between Chinese and Caucasian subjects. [ABSTRACT FROM AUTHOR]

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses. [ABSTRACT FROM AUTHOR]

Since the original publication of the article 'Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives' in March 2011 (see Appendix),1 there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.2 Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long-term continuous ustekinumab treatment through up to three years3,4 and four years5 of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.6-8 This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,9,10 Korean,11,12 and Taiwanese11,12 patients as those observed in trials conducted in mostly White populations in North America and Europe.6-8 These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented13 and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,14 and three phase 3 studies in Crohn's disease are currently in progress. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies conducted in the mid-1990s reported strong association and causality between the T-cell helper (TH) 1 inductor cytokine interleukin (IL)-12 and numerous immune-mediated disorders, which spurred the development of therapeutic agents targeting IL-12 function. One of the first to enter the clinic, ustekinumab, is a human monoclonal antibody (mAb) that binds to the p40 subunit of IL-12. Subsequent to the generation of ustekinumab, it was discovered that IL-23 also contains the p40 subunit. Thus, although ustekinumab was designed to target IL-12, it also modulates IL-23, a cytokine important to the development and/or maintenance of TH17 cells. Clinical observations established that IL-12/23p40 is integral to the pathologies of psoriasis, psoriatic arthritis and Crohn's disease. The molecular and cellular evaluations conducted in ustekinumab clinical programs have provided numerous insights into the pathologic processes of these disorders, illustrating how a novel molecular entity can contribute to our understanding of disease. The individual contributions of these cytokines to specific pathologies require investigation and clinical evaluation of the role of IL-12- and IL-23-specific inhibitors. [ABSTRACT FROM AUTHOR]

Golimumab is a human immunoglobulin G1κ monoclonal antibody that binds with high affinity and specificity to tumor necrosis factor-α. The objective of this study was to establish an approach for exposure-response modeling for golimumab in patients with rheumatoid arthritis using the American College of Rheumatology index of improvement (ACRN) as a measure of change in disease severity. Data were collected from 302 patients in the phase III GO-FORWARD trial who received golimumab or placebo plus methotrexate (background therapy) every 4 weeks through week 52. A latent-variable (unobservable) approach was used with an inhibitory indirect response model to link the placebo (methotrexate) effect and golimumab concentrations to ACRN scores. A model parameterization was proposed to allow deterioration beyond baseline and maintain mechanistic interpretability of the population-based indirect response model. The modeling was conducted using a sequential pharmacokinetic/pharmacodynamic approach. None of the covariate factors evaluated (demographics, disease characteristics, comorbidities, or concomitant medications) significantly improved the model fits. Likelihood profiling and a bootstrap analysis were used to assess parameter estimation precision, with their suitability discussed. The approach can be readily extended to model other types of clinical (efficacy or safety) scores with either an upper or a lower boundary. [ABSTRACT FROM PUBLISHER]

The development of ustekinumab as a first-in-class anti-interleukin (IL) 12/23p40 therapeutic agent for psoriasis represents an important example of modern and rational drug design and development. Psoriasis is a chronic, systemic, immune-mediated skin disorder with considerable clinical, psychosocial, and economic burden. Ustekinumab is a human monoclonal antibody (mAb) that binds the p40 subunit common to IL-12 and IL-23, key cytokines in psoriasis pathogenesis. The therapeutic mAb was developed using human gamma-1 immunoglobulin (IgG)-expressing transgenic mice, which created a molecule with endogenous IgG biologic properties and low immunogenicity. Ustekinumab was well tolerated in clinical studies and yielded rapid, significant, and sustained efficacy plus improved quality of life/work performance and reduced depression/anxiety. Its pharmacologic properties afford the most convenient dosing regimen among approved biologics, representing a significant advancement in the treatment of moderate to severe psoriasis. Ustekinumab also holds promise for other immune-mediated disorders with significant unmet need. [ABSTRACT FROM AUTHOR]

Biological agents are used to treat a variety of diseases in many therapeutic areas, including oncology, rheumatology, gastroenterology, dermatology, respiratory disease, hormone deficiency and infection. While biologics constitute many of the recently approved new therapies, clinical research of drug–drug interactions with biologics has been scant. This review presents a risk-based assessment strategy for evaluating drug–drug interactions with monoclonal antibodies, a predominant class of therapeutic biologics. The key parameters of this strategy are described here, as well as suggested studies that should be considered as part of the overall drug development process for therapeutic biologics. [Copyright &y& Elsevier]

Background/Purpose: To assess the pharmacokinetics (PK) and PK-efficacy correlations of body surface area (BSA)-adjusted dosing of 30 mg/m2 golimumab administered subcutaneously (SC) every 4 weeks (q4w) + methotrexate (MTX) through Week 48 in pediatric patients (ages 2 to <18 years) with juvenile idiopathic arthritis (JIA). Methods: GO-KIDS is a randomized-withdrawal, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial of SC golimumab 30 mg/m2 (maximum 50 mg) q4w + MTX (10/N30 mg/m2/week) in pediatric patients with active JIA despite current MTX therapy (median 15 mg/week). PK, safety, and efficacy evaluations were performed q4w through week 16. At Week 16, patients who were ACR JIA 30 responders were randomized (1:1) to 30 mg/m2 golimumab or placebo q4wks through Week 48 with GLM reinstituted upon flare (defined as per JIA ACR flare criteria) or initiation of new DMARDS, biologics, systemic immunosuppressives. Serum trough concentrations were also obtained at Weeks 12, 16, 24 and 48. Serum golimumab trough concentrations for 154 patients were determined via a validated immunoassay. The relationships of ACR pediatric 30 response and disease flare status with steady-state trough levels at Week 48 were assessed. Results: Trough serum golimumab concentrations in patients receiving SC 30 mg/m2 golimumab q4w through Week 48 were maintained over time. Steady-state trough golimumab levels were similar across different age groups, and were also similar to those seen in adult RA patients who received 50 mg SC q4w in Phase III clinical trials. There were no apparent differences in pediatric ACR JIA 30 response rates and disease flare rates among the 4 groups of JIA patients categorized by the 4 quartiles of steady-state trough golimumab levels at Week 48. In addition, there were no apparent PK differences between patients who did and did not experience disease flares in the randomized golimumab group. Mean (SD) and median trough serum golimumab concentrations (mg/mL) by age groups and body weight quartiles are presented in the . [ABSTRACT FROM AUTHOR]

Abstract: A large number of monoclonal antibody-based therapeutic proteins have emerged from the biopharmaceutical pipelines in recent years. Compared to small-molecule drugs, therapeutic proteins often confer a more targeted mechanism of action, with the potential for greater efficacy and fewer side effects. Over the recent decade, therapeutic proteins have gained an increasingly important place in the management of various diseases, including many of those that are referred to as “refractory” or “recalcitrant” to conventional therapies. In order to improve the well-being of pediatric patients and provide additional options for unmet medical needs, it is imperative to develop these innovative biotherapeutics for clinical use in children. This article provides an overview of the approved and emerging antibody-based therapeutic proteins with pediatric indications, the similarities and dissimilarities in pharmacokinetics, pharmacodynamics and immunogenicity of therapeutic proteins between children and adults, and strategies to develop therapeutic proteins in pediatric settings with emphasis on dose selection and rational use. In the context of a pediatric dosing strategy, the use of quantitative pharmacokinetic/pharmacodynamic modeling approaches to bridge the information gap between children and adults is also discussed. [Copyright &y& Elsevier]

Abstract: 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. ClinialTrials.gov identifier: NCT01362153. [Copyright &y& Elsevier]