Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. METHODS: We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. RESULTS: Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 µg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. CONCLUSIONS: In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

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.

Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis.

BACKGROUND & AIMS: We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis. METHODS: We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response. RESULTS: Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 µg/mL infliximab at week 8 of induction therapy and 3.7 µg/mL at steady-state during maintenance therapy produced optimal outcomes in patients. CONCLUSIONS: Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.

Pharmacokinetics and immunogenicity investigation of a human anti-interleukin-17 monoclonal antibody in non-naïve cynomolgus monkeys.

The pharmacokinetics (PK) of biologic therapeutics, especially monoclonal antibodies (mAbs), in monkeys generally presents the most relevant predictive PK information for humans. However, human mAbs, xenogeneic proteins to monkeys, are likely to be immunogenic. Monkeys previously treated with a human mAb (non-naïve) may have developed antidrug antibodies (ADAs) that cross-react with another test mAb in subsequent studies. Unlike PK studies for small-molecule therapeutics, in which animals may be reused, naïve monkeys have been used almost exclusively for preclinical PK studies of biologic therapeutics to avoid potential pre-existing immunologic cross-reactivity issues. The propensity and extent of pre-existing ADAs have not been systematically investigated to date. In this study, the PK and immunogenicity of mAb A, a human anti-human interkeukin-17 mAb, were investigated in a colony of 31 cynomolgus monkeys previously exposed to other human mAbs against different targets. We screened the monkeys for pre-existing antibodies to mAb A prior to the PK study and showed that 44% of the monkeys had pre-existing cross-reactive antibodies to mAb A, which could affect the PK characterization of the antibody. In the subcolony of monkeys without measurable pre-existing ADAs, PK and immunogenicity of mAb A were successfully characterized. The impact of ADAs on mAb A PK was also demonstrated in the monkeys with pre-existing ADAs. Here we report the results and propose a pragmatic approach for the use of non-naïve monkeys when conducting PK studies of biologic therapeutics.

Safety, tolerability and pharmacokinetics of a human anti-interleukin-13 monoclonal antibody (CNTO 5825) in an ascending single-dose first-in-human study.

AIMS: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 5825 following single-dose intravenous (i.v.) and subcutaneous (s.c.) administration in healthy and healthy atopic subjects. METHODS: Sixty-four subjects received a single dose of placebo or CNTO 5825 (0.1, 0.3, 1.0, 3.0, or 10 mg kg(-1) i.v. in a dose-escalating manner, or 3.0 mg kg(-1) s.c. in healthy subjects; and 10 mg kg(-1) i.v. in healthy atopic subjects). Subjects were observed for 96 h postadministration and followed for 16 weeks. Safety and tolerability were monitored, and serum samples were collected to measure CNTO 5825 concentrations, antibodies to CNTO 5825 and PD biomarkers. RESULTS: Most adverse events were mild to moderate in severity and considered to be unrelated to CNTO 5825, with no dose-dependent trends seen. The two serious adverse events were considered to be unrelated to CNTO 5825. After i.v. administration, CNTO 5825 exhibited linear PK, with a terminal half-life of ∼22-32 days. After a single 3 mg kg(-1) s.c. dose in healthy subjects, CNTO 5825 was absorbed into the systemic circulation with a median time to maximum serum concentration (tmax) of 5.45 days and absolute bioavailability of ∼75%. The PK profile of CNTO 5825 at 10 mg kg(-1) was similar in both healthy and healthy atopic subjects. No antibodies to CNTO 5825 were detected through week 16. In the CNTO 5825-treated healthy atopic subjects, there was a significant reduction in serum IgE and C-C motif chemokine ligand 17 (P = 0.028 and 0.068 vs. placebo, respectively). CONCLUSIONS: CNTO 5825 was well tolerated, had an acceptable safety profile, exhibited linear PK characteristics, and no detected antibodies to CNTO 5825.

Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects.

OBJECTIVE: Sirukumab (CNTO 136) is a human mAb with high affinity and specificity for binding to interleukin-6. This Phase 1 study evaluated the pharmacokinetics, immunogenicity, safety, and tolerability of sirukumab following a single subcutaneous (s.c.) administration in healthy male Japanese and Caucasian subjects. METHODS: Japanese and Caucasian subjects were randomized to placebo or 25, 50, or 100 mg sirukumab. Blood samples were collected to measure serum sirukumab concentration and antibodies to sirukumab. Noncompartmental analysis and population pharmacokinetic modeling were conducted to characterize sirukumab pharmacokinetics. Adverse events were monitored at each visit. RESULTS: 25 Japanese and 24 Caucasian subjects received sirukumab and were included in the pharmacokinetic evaluation. Mean Cmax and AUC0-∞of sirukumab increased in an approximately dose-proportional manner in both Japanese and Caucasian subjects. Median tmax was 3 -5 days after s.c. administration of sirukumab. Mean t1/2 was 15 -16 days in Japanese and 15 -18 days in Caucasian subjects. A one-compartment population pharmacokinetic model adequately described sirukumab pharmacokinetics following s.c. administration. The estimated population means for CL/F, V/F, and Ka were 0.54 ±0.03 l/day, 12.2 ±0.55 l, and 0.77 ±0.07 day-1, respectively. Race was not a significant covariate on CL/F or V/F. No subject was positive for antibodies to sirukumab. Adverse events were generally mild and did not appear to be dose-related or lead to study discontinuation. CONCLUSIONS: Sirukumab pharmacokinetics following subcutaneous administration was linear at doses ranging 25 -100 mg and was comparable between Japanese and Caucasian subjects. A single subcutaneous administration of 25, 50, or 100 mg sirukumab appeared to be well tolerated by both Japanese and Caucasian healthy male subjects.

Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Interleukin (IL)-6 is a cytokine known for pleiotropic and pro-inflammatory functions. IL-6 is involved in various disease processes including lupus erythematosus, rheumatoid arthritis, insulin resistance and malignancy. Anti-IL-6 receptor therapy has recently been demonstrated to be effective in the treatment of patients with rheumatoid arthritis. WHAT THIS STUDY ADDS: Sirukumab, a human monoclonal antibody against soluble IL-6, has been found to bind to human IL-6 with high affinity and specificity and thus suppress the biological activity of IL-6. Preclinical studies have demonstrated the safety of sirukumab in cynomolgus monkeys, a toxicologically relevant animal species, following repeated intravenous and subcutaneous administrations. This study shows that sirukumab has desirable pharmacokinetic characteristics (linear pharmacokinetics with long half-life), a low incidence of immunogenicity and a well-tolerated safety profile in healthy subjects, supporting further development of sirukumab as a potentially valuable therapeutic agent. AIMS: To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects. METHODS: Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg(-1) in a dose-escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab. RESULTS: Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both C(max) and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V(1)), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V(2)) were 0.364 l day(-1), 3.28 l, 0.588 l day(-1) and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose-response relationship was observed. No subjects were positive for antibodies to sirukumab. CONCLUSIONS: Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg(-1) in healthy subjects.

Bounded outcome score modeling: application to treating psoriasis with ustekinumab.

Disease status is often measured with bounded outcome scores (BOS) which report a discrete set of values on a finite range. The distribution of BOS data is often non-standard, e.g., J- or U-shaped, thus making standard analysis methods that assume normality inappropriate. Data transformations aiming to achieve normality with BOS can be much more difficult than with many other types of skewed distributions, and application of methodologies explicitly dealing with this problem has not been previously published in pharmacokinetic/pharmacodynamic modeling literature. In this analysis, a coarsened latent variable (CO) approach is augmented with flexible transformations and applied for the purpose of demonstrating ustekinumab effects on four clinical components (involved body surface area, induration, erythema, and scaling) in patients with moderate to severe psoriasis from two Phase 3 studies. Patients were randomized to receive placebo or ustekinumab 45 or 90 mg, followed by randomized withdrawal and long-term extension periods. The approach was used together with a previously established novel semi-mechanistic, mixed-effect exposure-response model integrated with placebo effect and disease progression, and with potential influence of dropout investigated. An additional transformation further modifying both tails of the standard logit transformation in the original CO approach was shown to be necessary in this application.

A latent variable approach for modeling categorical endpoints among patients with rheumatoid arthritis treated with golimumab plus methotrexate.

The need for accurate exposure-response modeling is critical in the drug development process. Few methods are available for linking discrete endpoints, especially ordered categorical variables, to mechanistic (e.g., indirect response) models. Here we describe a latent-variable approach that is proposed in conjunction with an inhibitory indirect response model to link the placebo/comedication effect and drug exposure to the endpoints. The model is parsimonious, with desirable characteristics at initial timepoints, and allows simultaneous modeling of multiple endpoints that are categorically ordered. Application of the model is demonstrated with data from a phase 3 clinical trial of golimumab, a human IgG1kappa monoclonal antibody that binds with high affinity and specificity to tumor necrosis factor (TNF)-alpha, in patients with rheumatoid arthritis. The efficacy endpoints were 20, 50, and 70% improvement in the American College of Rheumatology criteria (ACR20, ACR50, and ACR70, respectively) as measures of improvement in disease severity. The modeling results were shown to be consistent by using either a sequential or simultaneous pharmacokinetic/pharmacodynamic modeling approach. The suitability of likelihood profiling and proper use of bootstrap methods in assessing parameter estimation precision are also presented. More accurate, parsimonious models with appropriately quantified uncertainty can facilitate better drug development decisions.

Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis.

The population pharmacokinetics of ustekinumab are characterized in patients with moderate to severe plaque psoriasis in 2 Phase 3 studies (PHOENIX 1 and PHOENIX 2). Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent volume of distribution, and absorption rate constant from the final covariate model are 0.465 L.day(-1) (2.0%), 15.7 L (2.0%), and 0.354 day(-1) (16.2%), respectively. The interindividual variabilities for apparent clearance and apparent volume of distribution are 41.0% and 33.2%, respectively. Of the factors evaluated in this analysis, body weight, diabetes, and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and/or apparent volume of distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.

Population pharmacokinetics of golimumab, an anti-tumor necrosis factor-alpha human monoclonal antibody, in patients with psoriatic arthritis.

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.

Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis.

PURPOSE: Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population. METHODS: Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM. RESULTS: A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value +/- standard error), based on the final covariate model, were clearance (CL: 0.407 +/- 0.0103 L/day), apparent volumes of distribution in the central (V(1): 3.29 +/- 0.0679 L) and peripheral (V(2): 4.13 +/- 0.16 L) compartments, and intercompartment clearance (Q: 7.14 +/- 0.489 L/day). Infliximab exhibited interindividual variability for CL and V(1) of 37.7% and 22.1%, respectively. Infliximab t(1/2) is approximately 14 days. Covariate analysis showed that V(1) increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population. CONCLUSIONS: The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.

Population pharmacokinetics of infliximab in patients with ankylosing spondylitis.

The population pharmacokinetics of infliximab were characterized in patients with active ankylosing spondylitis (n = 274). Serum infliximab concentration data, from a 2-year period, were analyzed using NONMEM. A 2-compartment linear pharmacokinetic model was chosen to describe the pharmacokinetic characteristics of infliximab in serum. Population estimates (typical value +/- standard error) were obtained from the final covariate model: clearance (CL: 0.273 +/- 0.007 L/day), volume of distribution in the central compartment (V(1): 3.06 +/- 0.057 L), intercompartment clearance (Q: 1.72 +/- 0.48 L/day), and volume of distribution in the peripheral compartment (V(2): 2.94 +/- 0.17 L). Interindividual variability for CL and V(1) was 34.1% and 17.5%, respectively. White blood cell count at baseline and the antibody-to-infliximab status were significant covariates to CL; body surface area and sex were significant covariates to V(1). The CL for patients with a positive antibody-to-infliximab status was estimated to be 41.9% to 76.7% higher than for the remaining patients. Other covariates (baseline disease activity and the concomitant medication use of prednisolone, omeprazole, nonsteroidal anti-inflammatory drugs, or analgesics) did not affect infliximab pharmacokinetics. The development of antibodies to infliximab was associated with accelerated infliximab clearance and may represent a potential underlying mechanism for an inadequate response, or loss of response, to infliximab treatment.

Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.

PURPOSE: A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. RESULTS: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. CONCLUSIONS: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents.

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure-response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

Alpha-v integrins as therapeutic targets in oncology.

Integrins are heterodimeric cell adhesion receptors that mediate intercellular communication through cell-extracellular matrix interactions and cell-cell interactions. Integrins have been demonstrated to play a direct role in cancer progression, specifically in tumor cell survival, tumor angiogenesis, and metastasis. Therefore, agents targeted against integrin function have potential as effective anticancer therapies. Numerous anti-integrin agents, including monoclonal antibodies and small-molecule inhibitors, are in clinical development for the treatment of solid and hematologic tumors. This review focuses on the role of alpha(v) integrins in cancer progression, the current status of integrin-targeted agents in development, and strategies for the clinical development of anti-integrin therapies.

Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development.

Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs are large molecular weight glycoproteins that embody structural, biochemical, and pharmacologic properties distinct from other biologics or chemically synthesized compounds. Early therapeutic Mabs were murine proteins, and clinical testing of these agents revealed serious immune-mediated toxicities. The side effect profile of murine Mab therapeutic agents restricted the clinical development of these agents to indications with high morbidity and/or mortality (ie, oncology, graft vs host rejection). Advances in genetic engineering and protein expression technologies resulted in the development of Mabs composed either predominately (ie, mouse/human chimeric, "humanized") or completely (ie, "fully human" Mabs) of the human amino acid sequence. The production of chimeric, humanized, and fully human Mabs significantly reduced the immune-mediated toxicities and expanded the utility for these agents in numerous therapeutic areas, particularly in chronic disorders requiring either long-term administration (ie, rheumatoid arthritis) or treatment upon the flare up of disease (Crohn's disease, psoriasis). This review provides an overview of the molecular, biochemical, and pharmacokinetic properties and clinical development history of Mabs and details how these factors currently affect the scope and design of early clinical development strategies for these drug candidates. Emphasis is placed on the criteria for selecting appropriate subject populations for phase I testing of Mabs.

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.

Modification of the Fc Region of a Human Anti-oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half-life in Cynomolgus Monkeys.

The purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T1/2 ), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two-compartment population PK model with first-order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V1 ) = 31.3 mL/kg, volume of distribution of peripheral compartment (V2 ) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T1/2 = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V1 = 39.8 mL/kg, V2 = 32.6 mL/kg, F = 0.75 and T1/2 = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V1 +V2 ) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T1/2 of CNTO 8212 was significantly (p < 0.05) longer by about 2.7-fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti-OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half-life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1-20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half-life in human beings and may likely allow less frequent dosing in the clinical setting.

Pharmacokinetics and Exposure-response Relationship of Golimumab in Patients with Moderately-to-Severely Active Ulcerative Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies.

BACKGROUND AND AIMS: To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies. METHODS: We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT-subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and efficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing. ER relationships were assessed using trend, logistic regression, and receiver-operating-characteristic curve analyses. RESULTS: Median SGCs peaked at induction wk2 for golimumab 100/50mg, 200/100mg, and 400/200mg. Wk6 median SGCs were 0.78, 1.78, and 4.01 µg/ml, respectively. SGCs were sustained, reaching steady state approximately 8wks after golimumab maintenance commenced [wk14 of golimumab] regardless of induction dose. Median trough SGCs from maintenance wks8-44 ranged from 0.69 to 0.83 µg/ml [50 mg] and 1.33-1.58 µg/ml [100 mg]. SGCs were approximately dose proportional, and higher SGCs were associated with higher efficacy response rates during induction and maintenance. Factors associated with golimumab exposure were body weight, antibody-to-golimumab status, serum albumin, alkaline phosphatase, faecal markers, C-reactive protein, and pancolitis. SGCs of 2.5 µg/ml [induction wk6] and 1.4 µg/ml [maintenance steady-state trough] are potential target concentrations. Immunomodulators had no apparent impact on SGC with golimumab 100mg, whereas drug levels were slightly higher with golimumab 50mg with vs without immunomodulators. CONCLUSIONS: SGCs are approximately dose proportional, and a positive SGC-efficacy relationship exists during induction/maintenance golimumab treatment of adult UC patients. Optimal SGC targets require validation in prospective studies.