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Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11?-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

ABSTRACT: Inhibition of the enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11?-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Nonlinear, more than dose-proportional PKs were observed for ASP3662 after single-dose administration, particularly at lower doses (? 6 mg); the PKs at steady state were dose proportional, although the time to ASP3662 steady state was dose dependent at lower doses (? 2 mg). Similar PKs were observed among young Japanese, young non-Japanese, and elderly non-Japanese subjects. Specific inhibition of 11?-HSD1 occurred after both single and multiple doses of ASP3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP3662. ASP3662 was generally safe and well tolerated.

SUBMITTER: Bellaire S

PROVIDER: S-EPMC6510378 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

Bellaire Susan S Walzer Mark M Wang Tianli T Krauwinkel Walter W Yuan Nancy N Marek Gerard J GJ

Clinical and translational science 20190227 3

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11β-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Nonlinear, more than dose-proportional PKs were obs ...[more]

PMID: 30740895

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Project description:BACKGROUND: Preclinical studies have demonstrated that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a combination of plerixafor and low-dose tacrolimus (MRG-001) improves wound healing, promotes tissue regeneration and prevents allograft rejection. This first‐in‐human phase I dose‐escalation study evaluates the safety, tolerability, pharmacokinetics and pharmacodynamics of MRG-001, a novel fixed-dose combination drug. METHODS: In this Phase 1, double‐blind, randomized, placebo-controlled study, multiple ascending dose (MAD) cohorts are randomized to receive MRG-001 containing up to 0.02 mL/kg (plerixafor 24 mg/mL and tacrolimus 0.5 mg/mL) or saline placebo, subcutaneously every other day (SC, QAD) for 5 days (ClinicalTrials.gov: NCT04646603)The primary outcome is safety and tolerability. Safety and functional assessments are performed throughout the study. Blood samples are collected to evaluate systemic exposure. Fluorescence-activated cell sorting analysis and RNA expression of peripheral blood mononuclear cells (PBMCs) are used to evaluate the pharmacodynamics. RESULTS: Fourteen subjects received MRG-001 and 7 received a placebo. MRG-001 is safe and well-tolerated over the selected dose range. No deaths or severe adverse events are reported. There are no clinically significant laboratory changes after MRG-001 administration, apart from the predicted generalized leukocytosis. The intermediate dose group (0.01 mL/kg) showed the most significant white blood cell mobilization over time and increased by 2-4 fold from baseline and returned to baseline levels prior to the next injection. Circulating immune cells including FOXP3+ regulatory T cells and hematopoietic stem cells (CD45IntCD34+) increased significantly after MRG-001 injection. PBMC RNA sequencing and gene set enrichment analysis revealeds 31 down-regulated pathways in the intermediate dose MRG-001 group compared to no changes in the placebo group. CONCLUSION: MRG-001 is safe and well-tolerated across the full dose ranges tested. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration. A Phase II trial to treat severely and critically ill COVID-19 patients with MRG-001 has been initiated (NCT04646603) and a second phase II trial will explore the potential of MRG-001 to accelerate wound healing (NCT05844527),

Dataset Information

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11?-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

Publications

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

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