Assessment of the Pharmacokinetics and Safety of Spesolimab, a Humanised Anti-interleukin-36 Receptor Monoclonal Antibody, in Healthy Non-Japanese and Japanese Subjects: Results from Phase I Clinical Studies
Background and Objective The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of sin...
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| Published in: | Clinical pharmacokinetics Vol. 61; no. 12; pp. 1771 - 1787 |
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01.12.2022
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| ISSN: | 0312-5963, 1179-1926, 1179-1926 |
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| Abstract | Background and Objective
The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects.
Methods
Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed.
Results
Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01–0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3–5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150–600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration–time profile in 26.7–33.3% and 16.7–37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers.
Conclusions
The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases.
Clinical Trial Registration
For Studies 1–5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835. |
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| AbstractList | The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects.
Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed.
Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01-0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3-5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150-600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration-time profile in 26.7-33.3% and 16.7-37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers.
The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases.
For Studies 1-5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835. The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects.BACKGROUND AND OBJECTIVEThe interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects.Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed.METHODSFive phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed.Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01-0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3-5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150-600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration-time profile in 26.7-33.3% and 16.7-37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers.RESULTSIntravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01-0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3-5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150-600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration-time profile in 26.7-33.3% and 16.7-37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers.The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases.CONCLUSIONSThe pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases.For Studies 1-5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835.CLINICAL TRIAL REGISTRATIONFor Studies 1-5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835. Background and Objective The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluatethe pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects.Methods Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed.Results Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01-0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3-5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150-600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration-time profile in 26.7-33.3% and 16.7-37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers.Conclusions The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases. Background and Objective The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects. Methods Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed. Results Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01–0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3–5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150–600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration–time profile in 26.7–33.3% and 16.7–37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers. Conclusions The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases. Clinical Trial Registration For Studies 1–5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835. |
| Author | Joseph, David Li, Xiujiang Thoma, Christian Haeufel, Thomas |
| Author_xml | – sequence: 1 givenname: David surname: Joseph fullname: Joseph, David organization: Boehringer Ingelheim Pharmaceuticals, Inc – sequence: 2 givenname: Christian surname: Thoma fullname: Thoma, Christian organization: Boehringer Ingelheim International GmbH – sequence: 3 givenname: Thomas surname: Haeufel fullname: Haeufel, Thomas organization: Boehringer Ingelheim International GmbH – sequence: 4 givenname: Xiujiang surname: Li fullname: Li, Xiujiang email: xiujiang.li@boehringer-ingelheim.com organization: Boehringer Ingelheim Pharmaceuticals, Inc |
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| CitedBy_id | crossref_primary_10_1007_s12325_024_02940_8 crossref_primary_10_1016_j_det_2024_08_001 crossref_primary_10_1080_14740338_2023_2265295 crossref_primary_10_1177_10600280241252688 crossref_primary_10_1007_s10875_023_01632_2 crossref_primary_10_3389_fimmu_2024_1359481 crossref_primary_10_1016_j_jid_2023_11_004 crossref_primary_10_1111_ijd_16941 |
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The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective,... The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody... Background and Objective The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective,... |
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| SubjectTerms | Antibodies Cytokines Dermatitis Dose-Response Relationship, Drug Double-Blind Method Drug dosages Half-Life Healthy Volunteers Humans Inflammatory diseases Infusions, Intravenous Injections, Subcutaneous Internal Medicine Laboratories Medicine Medicine & Public Health Monoclonal antibodies NCT NCT02525679 NCT02852824 NCT03100903 NCT03123094 NCT03617835 Original Original Research Article Pathogenesis Pharmacokinetics Pharmacology Pharmacology/Toxicology Pharmacotherapy Plasma |
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| Title | Assessment of the Pharmacokinetics and Safety of Spesolimab, a Humanised Anti-interleukin-36 Receptor Monoclonal Antibody, in Healthy Non-Japanese and Japanese Subjects: Results from Phase I Clinical Studies |
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