Pharmacokinetics of Niacin, Simvastatin and their Metabolites in Healthy Chinese Subjects after Single and Multiple Doses of a Fixed Dose Combination Tablet of Niacin Extended Release/Simvastatin

Abstract

Objective: A fixed dose combination tablet of niacin extended release (ER)/simvastatin was recently developed in China. This study was designed to assess and compare the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects after single and multiple doses administration.

Methods: From day 1 to day 7, 12 Chinese subjects were given a tablet every day at approximately 10 p.m. Serial blood samples were collected. Niacin and nicotinuric acid (NUA) in plasma, niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) in urine, simvastatin and simvastatin acid in plasma were determined by LC/MS/MS methods. Pharmacokinetic parameters on days 1 and 7 were compared.

Results:The main pharmacokinetic parameters for the single and multiple doses were as ­follows: Niacin: T_max were 3.8±1.5 h and 3.9±2.0 h; C_max were 2 091±1 315 ng/ml and 2 323±1 542 ng/ml; AUC_0-t were 4 123.88±3 138.48 ng ∙ h/ml and 4 385.98±3 127.05 ng ∙ h/ml. NUA: T_max were 4.7±1.7 h and 3.8±1.5 h; C_max were 1 057±549 ng/ml and 1 087±470 ng/ml; AUC_0-t were 4 012.49±2 168.68 ng ∙ h/ml and 4 040.45±1 886.57 ng ∙ h/ml. Simvastatin: T_max were 1.8±1.0 h and 2.5±2.5 h; C_max were 3.15±1.67 ng/ml and 4.87±4.11 ng/ml; AUC_0-t were 9.03±5.10 ng ∙ h/ml and 17.63±13.93 ng ∙ h/ml. Simvastatin acid: T_max were 5.8±1.7 h and 6.5±1.4 h; C_max were 4.22±2.10 ng/ml and 9.30±8.09 ng/ml; AUC_0-t were 34.65±16.89 ng ∙ h/ml and 61.62±46.41 ng ∙ h/ml. Urine Recovery rate of total niacin: (40.55±7.38)% and (62.87±12.04)%.

Conclusion: Compared with those after a single dose, pharmacokinetics of niacin and NUA was similar; total urine recovery of niacin was higher; exposure to simvastatin and simvastatin acid were higher following multiple doses.

Key words

niacin - nicotinuric acid - simvastatin - simvastatin acid - pharmacokinetics

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