Dataset Information

Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

ABSTRACT: TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median t_max , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.

SUBMITTER: Cohen-Barak O

PROVIDER: S-EPMC5516185 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

Cohen-Barak Orit O Barkay Hadas H Rasamoelisolo Michele M Butler Kathleen K Yamada Kazumasa K Bassan Merav M Yoon Esther E Spiegelstein Ofer O

Clinical pharmacology in drug development 20160921 4

TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian pop ...[more]

PMID: 27489211

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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.

Project description:Background and objectivesRotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson's disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.MethodsIn this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration-time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values).ResultsThe pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0±0.5 mg for Japanese subjects and 2.08±0.58 mg for Caucasians. Plasma concentration-time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine=unconjugated rotigotine+conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1% of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7% of absorbed dose in Japanese subjects and 10.8% of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1%, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5% in Japanese subjects and 4.2% Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics.ConclusionAdministration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.

Dataset Information

Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

Publications

Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

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