Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects

Zandvliet, Anthe S.; Glasgow, Shirley; Horowitz, Ann D.; Montgomery, Diana; Marjason, Joanne; Mehta, Anish; Xu, Christine; Vugt, Marianne van; Khalilieh, Sauzanne

doi:10.5414/cp202176

Cited by 21 publications

(15 citation statements)

References 15 publications

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“…In a previous study, the PK of tildrakizumab was similar in Japanese, Caucasian and Chinese subjects matched by age, sex, height, body weight and body mass index 23 . Furthermore, in the present study, the Japan region had no impact on the PASI response as a covariate.…”

Section: Discussionsupporting

confidence: 59%

Exposure–response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials

Kerbusch¹,

Wada

et al. 2020

Brit J Clinical Pharma

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Aims In this exposure–response analysis, the dosing regimen for tildrakizumab, an antibody for treating moderate‐to‐severe chronic plaque psoriasis, was determined using data from 3 randomised controlled trials (P05495/NCT01225731: phase 2b, n = 355; reSURFACE 1/NCT01722331: phase 3, n = 772; reSURFACE 2/NCT01729754: phase 3, n = 1090). Methods A maximum drug effect (Emax) logistic‐regression exposure–efficacy model was used to describe the week 12 Psoriasis Area and Severity Index (PASI) responses with average concentration of tildrakizumab during weeks 1–12 (Cavg12) as exposure metric. The impact of covariates (e.g., body weight, region) was tested. Exposure–safety, longitudinal pharmacokinetic–pharmacodynamic and risk–benefit analyses were also conducted. Results At week 12, Emax was estimated at 62.2, 37.9 and 14.6% of responders for PASI75/90/100, respectively. Exposure–response curves plateaued at exposures >5 μg mL−1. Heavier subjects had a lower response rate to placebo as measured by PASI75/90/100 than lighter subjects. PASI100 placebo response was less in subjects with higher baseline PASI score and older age. Simulated week 12 PASI75 increased by ≤4% on increasing the dose from 100 to 200 mg every 12 weeks (Q12W). The pharmacokinetic–pharmacodynamic model adequately described the time course of PASI change after treatment in the entire population and in each subject. Risk–benefit profiles were favourable for the 100‐ and 200‐mg doses in different weight subgroups. Conclusions Patients with moderate‐to‐severe psoriasis should receive 100‐mg subcutaneous tildrakizumab Q12W. Patients with high body weight (>90 kg) may benefit from a higher dose (200‐mg Q12W).

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Section: Discussionsupporting

confidence: 59%

Exposure–response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials

Kerbusch¹,

Wada

et al. 2020

Brit J Clinical Pharma

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“…32 Additionally, study on tildrakizumab, a humanized IgG1/k antieinterleukin-23 monoclonal antibody, found no impact of ethnic variability in white, Chinese, and Japanese patients. 33 Finally, a clinical research study by Uenaka et al 34 showed that the PK characteristics of solanezumab were similar in Japanese and white patients, with similar CL and Vd across doses. The findings from these studies together with our findings suggest that ethnicity is unlikely to affect the PK behavior of IgG and monoclonal antibodies.…”

Section: Discussionmentioning

confidence: 98%

Pharmacometric Analysis of IgPro10 in Japanese and Non-Japanese Patients With Primary Immunodeficiency

Luo

Baheti

Tortorici

et al. 2020

Clinical Therapeutics

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Purpose: Immunoglobulin (Ig) G replacement therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is the standard treatment in patients with primary immunodeficiencies (PID). We aimed to characterize the pharmacokinetic (PK) characteristics of serum IgG following administration of IgPro10 every 3 or 4 weeks in Japanese patients with PID, and compare with PK in non-Japanese patients. A previously developed population PK (PPK) model was validated, and predicted parameters were compared with the results from the clinical study. Methods: The previously developed PPK model, containing IgG concentration data from 5 non-Japanese studies, was supplemented with data from 3 Japanese studies of IgPro10 or IgPro20 to compare the IgG PK parameters between Japanese and non-Japanese patients. The model was externally validated by simulating IgG concentrationetime profiles in Japanese patients to predict serum IgG PK characteristics and to compare them with observed Japanese PK data from Study IgPro10_3004. Findings: The analysis included 4502 serum IgG concentration values (from 34 Japanese and 168 non-Japanese patients). PPK estimates from the current analysis demonstrated a clearance (CL) of 0.139 L/d, central volume (V2) of 4.01 L, inter-compartmental clearance (Q) of 0.30 L/d, and peripheral volume of 3.51 L. These results were consistent with those from the previously published PPK model, with similar bootstrap means and 95% CIs. Goodness-of-fit criteria indicated that the final PPK model was consistent with observed data, with no systemic bias in model prediction. Prediction-corrected visual predictive checks confirmed a good description of data on both SCIG and IVIG. PK parameters were equivalent between Japanese and non-Japanese patients. Body weight was determined to be a significant covariate on both CL and V2. Simulated and observed AUC and maximum and minimum serum IgG concentrations were similar, with 90% CIs overlapping between simulated and observed IgG concentrations in Japanese patients. Implications: PK parameter estimates of serum IgG were similar between Japanese and non-Japanese patients with PID. The PPK model, updated with Japanese data, was consistent with the previously published PPK model and could accurately predict both individual and population serum IgG concentrationetime profiles following IgPro10 IV infusions every 3 or 4 weeks. EudraCT identifier: 2016-001631-12.

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“…Two studies on tildrakizumab have shown the development of anti-drug antibodies (ADA) [196,197]. This may have significance in patients that would potentially have to take such therapies over an extended period of time, and therefore this may not be a clinically relevant issue with lung cancer.…”

Section: Expert Opinionmentioning

confidence: 98%

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

Joerger

Finn

Cuffe

et al. 2016

Expert Opinion on Therapeutic Targets

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There is strong pharmaceutical development of agents targeting the IL-17-TH17 pathway for the treatment of psoriasis (Ps) and psoriatic arthritis (PsA). Lung cancer accounts for 28% of all cancer-related deaths worldwide, and roughly 80% of patients with newly-diagnosed non-small cell lung cancer (NSCLC) present with metastatic disease, with a poor prognosis of around 12 months. Therefore, there is a high unmet medical need for the development of new and potent systemic treatments in this deadly disease. The emergence of immunotherapies such as anti-PD-1 or anti-PDL1 as candidate therapies in non-small cell lung cancer (NSCLC) indicates that targeting critical immuno-modulatory cytokines including those within the IL-17-Th1/Th17 axis may have proven benefit in the treatment of lung cancer. Areas covered: In this review we describe the current evidence for aberrant IL-17-Th1/Th17 settings in cancer, particularly with regard to targeting this axis in NSCLC. We further discuss the current agents under pharmaceutical development which could potentially target this axis, and discuss the current limitations and areas of concern regarding the use of these in lung cancer. Expert opinion: Current evidence suggests that moving forward agents targeting the IL-17-Th1/Th17 pathway may have novel new oncoimmunology indications in the treatment paradigm for NSCLC.

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Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects

Abstract: The pharmacokinetics of tildrakizumab were similar in Japanese, Caucasian, and Chinese subjects. Tildrakizumab exposure increased proportionally with dose in the range of 50-400 mg. A single SC dose of 50, 200, and 400 mg or a single IV dose of 10 mg/kg was generally well tolerated.

Cited by 21 publications

References 15 publications

Exposure–response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials

Exposure–response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials

Pharmacometric Analysis of IgPro10 in Japanese and Non-Japanese Patients With Primary Immunodeficiency

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

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