Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU-838) After Single and Multiple Ascending Oral Dos
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ORIGINAL RESEARCH ARTICLE
Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU‑838) After Single and Multiple Ascending Oral Doses in Healthy Male Subjects Andreas Muehler1 · Hella Kohlhof1 · Manfred Groeppel1 · Daniel Vitt1
© The Author(s) 2020
Abstract Background and Objective Vidofludimus is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The clinical efficacy and safety profile of vidofludimus has been analyzed in patients suffering from rheumatoid arthritis and Crohn’s disease and ulcerative colitis. In previous sudies, hematuria at higher doses occurred in close temporal relationship to vidofludimus administration and appeared to be dose related. The present report describes the results from two phase 1 studies conducted in healthy male subjects to investigate the safety, tolerability and pharmacokinetics after single and multiple ascending (SAD and MAD) oral doses of IMU-838 (vidofludimus calcium, tablets containing a specific polymorph). The effect of food on the pharmacokinetics of IMU-838 was also assessed in the SAD study. Methods In the SAD study, 12 subjects received single doses of IMU-838 under fasting (10–40 mg) or fed (10 mg) condition in an open-label, partial parallel group design. In the MAD study, 52 subjects received multiple doses of IMU-838 (30–50 mg) in a double-blind, placebo-controlled, parallel group design. Results IMU-838 showed dose-proportional pharmacokinetics after single and multiple oral dosing in both SAD and MAD studies. IMU-838 was well absorbed after single daily doses. Food did not impact the pharmacokinetics of IMU-838. The accumulation factor for multiple daily dosing was approximately 2. Steady-state concentrations were reached within about 6–8 days for 30–50 mg groups. The geometric mean plasma half-life of IMU-838 at steady state was approximately 30 h, which supports its use for once-daily dosing regimen. Single and multiple oral doses of IMU-838 were safe and well tolerated. Conclusion Overall, oral IMU-838 was generally well tolerated in SAD and MAD studies in healthy subjects over a wide dose range of 10–50 mg. IMU-838 was well absorbed after single daily doses. IMU-838 showed dose proportional pharmacokinetics after single and multiple oral dosing.
1 Introduction Vidofludimus, the active moiety and free acid form of IMU-838, is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which is only expressed at high levels and relevant in metabolically activated lymphocytes [1–3]. The activity of DHODH is the rate-limiting step in pyrimidine synthesis to support the enhanced nucleotide demand for Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13318-020-00623-7) contains supplementary material, which is available to authorized users. * Andreas Muehler [email protected] 1
Immunic AG, Am Klopferspitz 19, 82152 Planegg‑Martinsried, Germany
messenger ribonucleic acid (mRNA) and deoxyribo
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