Single- and Multiple-dose Pharmacokinetic, Safety and Tolerability Study of Mildronate Injection in Healthy Chinese Subjects Pharmacokinetic of Mildronate Injection

Abstract

Mildronate is an agent for cardioprotection and neuroprotection. This study aimed to evaluate the pharmacokinetic (PK) profiles, safety and tolerability of mildronate injection after single escalating doses and multiple doses in healthy Chinese subjects. We performed a randomized, open-label, single- and multiple-dose phase I trial including 3 doses of mildronate: 250, 500 and 750 mg. Plasma and urine samples were collected and concentrations of mildronate were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). PK parameters were calculated using noncompartmental analysis. Safety and tolerability was assessed throughout noting subjects’ vital signs and monitoring adverse events (AEs) and conduct a comprehensive physical examination and laboratory analyses before and after the study. There was no significant difference in C ₀, AUC_0-t, AUC_0-∞ among 3 single-dose groups, whereas T _1/2 had significant statistical difference which may be caused by the inhibition of metabolic enzymes. Single- and multiple-dose intravenous injection of mildronate exhibited linear PK profiles in the range of 250–750 mg. An unconspicuous accumulation phenomenon was found after multiple-dose mildronate administration. No significant gender difference was found and mildronate is primarily excreted by the kidney. No serious AEs were observed. The formulation was safe and well tolerated from 250 to 750 mg.

Key words

healthy Chinese subjects - mildronate injection - pharmacokinetics study - safety - tolerability

• References

• 1 Hayashi Y, Kirimoto T, Asaka N et al. Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. Eur J Pharmacol 2000; 395: 217-224
• 2 Liepinsh E, Vilskersts R, Skapare E. Mildronate decreasescarnitine availability and up-regulates glucose uptake and related gene expression in the mouse heart. Life Sci 2008; 83: 613-619
• 3 Binienda Z, Przybyla-Zawislak B, Virmani A et al. L-carnitine and neuroprotection in the animal model ofmitochondrial dysfunction. Ann N Y Acad Sci 2005; 1053: 174-182
• 4 Klusa V, Muceniece R, Isajevs S et al. Mildronateenhances learning/memory and changes hippocampal protein expressionin trained rats. Pharmacol Biochem Behav 2013; 106: 68-76
• 5 Beitnere U, Van Groen T, Kumar A et al. Mildronate Improves Cognition and Reduces Amyloid-b Pathology in Transgenic Alzheimer’s Disease Mice. Journal of Neuroscience Research 2014; 92: 338-346
• 6 Dambrova M, Liepinsh E, Kalvinsh I. Mildronate: Cardioprotective Action through Carnitine-Lowering Effect. Trends in Cardiovascular Medicine 2002; 6: 275-279
• 7 Simkhovich BZ, Meirena DV, Khagi KhB et al. Biochemical characteristics of the anti-ischemicaction of the new structural analog of gamma-butyrobetaine3-(2,2,2,-trimethylhydrazine)propionate. Farmakol Toksikol 1987; 50: 100-104
• 8 Sesti C, Simkhovich BZ, Kalvinsh I et al. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. J Cardiovasc Pharmacol 2006; 47: 493-499
• 9 Yoshisue K, Yamamoto Y, Yoshida K et al. Pharmacokinetics and biological fate of 3-(2,2,2-trimethylhydrazinium)propionate dihydrate (MET-88), a novel cardioprotective agent, in rats. Drug Metabolism and Disposition 2000; 28: 687-694
• 10 Zhang J, Cai LJ, Yang J et al. Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open-label, single- and multiple-dose study in healthy volunteers. Fundam Clin Pharmacol 2011; 27: 120-128
• 11 Peng Y, Yang J, Wang Z et al. Determination of mildronate by LC-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 551-556
• 12 Tars K, Rumnieks J, Zeltins A et al. Crystal structure of human gamma-butyrobetaine hydroxylase. Biochemical and Biophysical Research Communications 2010; 398: 634-639
• 13 Tars K, Leitans J, Kazaks A et al. Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase. Journal of Medicinal Chemistry 2014; 57: 2213-2236
• 14 Leung IK, Krojer TJ, Kochan GT et al. Structural and mechanistic studies on gamma-butyrobetaine hydroxylase. Chem Biol 2010; 17: 1316-1324