Dataset Information

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers.

ABSTRACT: Tropifexor (LJN452) is a potent, orally available, non-bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first-in-human study of tropifexor following single- and multiple-ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10- to 3000-µg tropifexor or placebo and 1 cohort receiving 300-µg tropifexor with a high-fat meal. The MAD study included 4 lean cohorts receiving 10 to 100 µg and 1 obese cohort receiving 30-µg once-daily doses or placebo for 14 days. Pharmacodynamic assessment of fibroblast growth factor 19 and fasting plasma lipids was performed after dosing. Overall, 95 volunteers received at least 1 tropifexor or placebo dose. Tropifexor was well tolerated up to 3000 µg and 100 µg in the SAD and MAD studies, respectively; however, 2 subjects discontinued the MAD study due to asymptomatic elevation of liver transaminases. At single doses, tropifexor showed a moderate rate of absorption (median time to maximum concentration, 4 hours), dose-proportional increases in exposure, and elimination half-life of 13.5 to 21.9 hours. When taken with food, tropifexor exposure increased by ?60%. With multiple dosing, steady state was reached on day 4 with <2-fold accumulation. Single and multiple doses showed dose-dependent increases in fibroblast growth factor 19. No changes in serum lipids were observed in tropifexor- vs placebo-treated obese subjects. In conclusion, tropifexor was well tolerated, had a pharmacokinetic profile suitable for once-daily dosing and showed dose-dependent target engagement without altering plasma lipids in healthy volunteers.

SUBMITTER: Badman MK

PROVIDER: S-EPMC7187203 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers.

Badman Michael K MK Chen Jin J Desai Sachin S Vaidya Soniya S Neelakantham Srikanth S Zhang Jie J Gan Lu L Danis Kate K Laffitte Bryan B Klickstein Lloyd B LB

Clinical pharmacology in drug development 20191210 3

Tropifexor (LJN452) is a potent, orally available, non-bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first-in-human study of tropifexor following single- and multiple-ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10- to 3000-µg tropifexor or placebo and 1 cohort receiving 300-µg tropifexor with a high-fat meal. The MAD study included 4 lean ...[more]

PMID: 31823525

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Project description:BACKGROUND:Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, a cytokine essential for the formation, function and survival of osteoclasts. This study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose denosumab (60 and 120 mg) in healthy Chinese volunteers. METHODS:This randomized (3:3:2), single-blind, placebo-controlled study enrolled healthy Chinese volunteers to receive single subcutaneous injection of denosumab 60 mg, 120 mg, or placebo. Study consisted of screening period (up to 21 days), treatment and assessment period (19 weeks), and an end-of-study visit (at week 26). Denosumab pharmacokinetics and pharmacodynamics parameters were estimated using non-compartmental analysis. Safety and tolerability were assessed throughout the study. RESULTS:A total of 63 volunteers received the study treatment and 62 (98.4%) completed the study. Denosumab serum concentrations peaked at around Day 10 with dose-proportional increase from 60 mg to 120 mg. The mean terminal half-life of denosumab 60 mg and 120 mg was 15 days and 26 days, respectively. The serum C-terminal cross-linking telopeptide of type I collagen concentration-time profiles were similar (>80% decrease within 5 days) between denosumab 60 mg and 120 mg groups. The most commonly reported adverse event (AE) was decreased blood calcium levels (denosumab 60 mg, n = 13; denosumab 120 mg, n = 13; placebo, n = 1); however only one volunteer had calcium level below the abnormality value of potential clinical importance and none of the volunteers developed symptoms of hypocalcemia. The majority of AEs were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. No clinically significant findings in vital signs or electrocardiogram were observed. CONCLUSIONS:Both denosumab 60 mg and 120 mg were well tolerated with no new safety concerns identified in healthy Chinese volunteers with similar pharmacokinetics and pharmacodynamics profiles to that of Caucasians. TRIAL REGISTRATION:ClinicalTrial.gov NCT02135640.

Dataset Information

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers.

Publications

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers.

Similar Datasets

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