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Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody, in healthy Japanese male subjects.

ABSTRACT: Interleukin 5 (IL-5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti-IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single-blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750?mg) or placebo. Subjects were observed for up to 151 days postdose, depending on the dose administered. Blood samples were collected to measure mepolizumab concentrations, blood eosinophils, IL-5, and antibodies to mepolizumab. Mepolizumab exhibited dose-proportional pharmacokinetics. The terminal phase half-life was 19.7-34.6 days, independent of dose. Higher mepolizumab plasma concentrations were associated with lower blood eosinophil counts. Mepolizumab 75-750?mg reduced blood eosinophils for ?3 months postdose. Mepolizumab demonstrated a favorable safety profile: of 41 reported adverse events, most were mild in severity and none were serious. No neutralizing antibodies to mepolizumab were detected. Sustained reduction in blood eosinophils after single intravenous mepolizumab doses ? 75?mg, along with mepolizumab pharmacokinetics and a favorable tolerability profile in healthy Japanese subjects, provides a solid foundation for future studies with mepolizumab in Japanese patients with asthma.

SUBMITTER: Tsukamoto N

PROVIDER: S-EPMC5042051 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody, in healthy Japanese male subjects.

Tsukamoto Naohiro N Takahashi Naoki N Itoh Hiroshi H Pouliquen Isabelle I

Clinical pharmacology in drug development 20150818 2

Interleukin 5 (IL-5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti-IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single-blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750 mg) or placebo. Subjects were ob ...[more]

PMID: 27138023

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Project description: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.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.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.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.Clinical trial registrationFor Studies 1-5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835.

Project description:BACKGROUND AND OBJECTIVE:Atacicept is an inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), and is being studied in relation to immunological disease. Currently, limited data on atacicept are available in non-Caucasian subjects. Pharmacokinetic data from earlier studies of atacicept were derived using an enzyme-linked immunosorbent assay (ELISA), which was subsequently found to have inadequacies. Hence, a new bioanalytical ELISA for total atacicept was developed and validated. We conducted this randomized, double-blind, placebo-controlled phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of atacicept in healthy Japanese and Caucasian subjects while generating pharmacokinetic data using the new ELISA. METHODS:Japanese subjects aged???18 to???55 years (n? =?24) were randomized (1:1:1:1) to a single subcutaneous dose of atacicept 25, 75, or 150 mg or placebo. Caucasian subjects were then enrolled to match the Japanese subjects' gender, body weight (±?20%), and height (±?15%). RESULTS:Atacicept was well tolerated and there were no clinically significant differences in treatment-emergent adverse events (TEAEs), vital signs, or laboratory parameters between the Japanese and Caucasian subjects. Most (90%) TEAEs were mild; no severe or serious TEAEs or deaths occurred. Weight-adjusted atacicept exposure was comparable between ethnicities and across doses: the Japanese/Caucasian ratio of the area under the serum concentration-time curve from time zero to the last sampling point (AUC0-t) was 107.21% (90% CI 93.42-123.02%) and the Japanese/Caucasian ratio of maximum serum concentration (Cmax) was 95.74% (90% CI 74.26-123.43%; ANCOVA). Median time to reach Cmax (tmax) was 20-60 h across all subjects. Dose-exposure relationships were comparable for the two ethnicities, with dose-normalized AUC0-t decreasing with increasing dose, indicating nonlinear pharmacokinetics for the doses examined. There were no statistically significant differences between ethnicities in the pharmacokinetics-dose relationship. Some transient dose-related decreases in mean serum immunoglobulin (Ig)A and IgM, but not IgG, were observed after atacicept administration. There were small transient increases in peripheral B cell numbers in the first 4 days after dosing that were larger with atacicept than with placebo, with no apparent dose relationship. No anti-atacicept antibodies were detected. CONCLUSION:The safety, pharmacokinetic, and pharmacodynamic profiles of atacicept in healthy Japanese subjects were comparable to those in healthy Caucasian subjects. EudraCT-ID: 2013-002703-34.

Dataset Information

Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody, in healthy Japanese male subjects.

Publications

Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody, in healthy Japanese male subjects.

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