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Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

ABSTRACT: Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150?mg (Caucasian males, 18-55?years), 25?mg (Caucasian males, > 65?years and Caucasian females, 18-55?years), 25, 50, 100 and 150?mg (Japanese males, 18-55?years). Study 2: Caucasian males (18-55?years) received 1, 2.5, 10 or 25?mg once daily TA-8995 or placebo for 21-28?days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests.Peak TA-8995 concentrations occurred approximately 4?h post-dose. Mean half-lives ranged from 81 to 166?h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25?mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated.TA-8995 is a potent CETP inhibitor and warrants further investigation.

SUBMITTER: Ford J

PROVIDER: S-EPMC4243901 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Ford John J Lawson Matt M Fowler David D Maruyama Nobuko N Mito Seiji S Tomiyasu Koichi K Kinoshita Shuji S Suzuki Chisa C Kawaguchi Atsuhiro A Round Patrick P Boyce Malcolm M Warrington Steve S Weber Werner W van Deventer Sander S Kastelein John J P JJ

British journal of clinical pharmacology 20140901 3

<h4>Aims</h4>Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.<h4>Methods</h4>Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Jap ...[more]

PMID: 24628035

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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),

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Dataset Information

Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Publications

Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

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