Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy fasted Chinese adult males

• Published in: Clinical therapeutics Vol. 32; no. 7; pp. 1396 - 1407
• Main Authors: Liu, Yan-Mei, MD, Pu, Hua-Hua, MD, Liu, Gang-Yi, MS, Jia, Jing-Ying, MS, Weng, Li-Ping, MS, Xu, Rong-Jing, MS, Li, Guo-Xiu, MD, Wang, Wei, MS, Zhang, Meng-Qi, BS, Lu, Chuan, BS, Yu, Chen, MS
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01-07-2010; Elsevier; Elsevier Limited
• Subjects: Administration, Oral; Adult; Area Under Curve; Asian Continental Ancestry Group; atorvastatin; Atorvastatin Calcium; Bioavailability; Bioequivalence; Biological and medical sciences; China; Chinese; Chromatography; Cross-Over Studies; Drug dosages; Drugs, Generic - administration & dosage; Drugs, Generic - adverse effects; Drugs, Generic - pharmacokinetics; Half-Life; Heptanoic Acids - administration & dosage; Heptanoic Acids - adverse effects; Heptanoic Acids - pharmacokinetics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Internal Medicine; liquid chromatography isotope-dilution mass spectrometry (LC-IDMS); Male; Mass spectrometry; Medical Education; Medical sciences; ortho-hydroxy-atorvastatin; pharmacokinetic; Pharmacokinetics; Pharmacology. Drug treatments; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - pharmacokinetics; Scientific imaging; Statins; Tablets; Therapeutic Equivalency; Young Adult; Asia; China; liquid chromatography isotope-dilution mass spectrometry (LC-IDMS); Chinese; pharmacokinetic; atorvastatin; bioequivalence; ortho-hydroxy-atorvastatin; Bioequivalence; Calcium; Pharmacotherapy; Male; Hypocholesterolemic agent; Inorganic element; Randomization; HMG-CoA reductase inhibitor; Tablet; Isotopes; Human; Drug; Evaluation; Healthy subject; Enzyme; Single dose; Enzyme inhibitor; Exploration; Statin derivative; Liquid chromatography; Crossover study; Treatment; Dosage form; Atorvastatin; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Pharmacokinetics; Mass spectrometry; Antilipemic agent
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2010.07.004

Abstract Background: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China. Objective: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers. Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including Cmax , Tmax , t½ , AUC0−t , and AUC0−∞ ), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the logtransformed ratios of AUC and Cmax of atorvastatin were within the predetermined bioequivalence range (0.80–1.25 for AUC and 0.70–1.43 for Cmax ) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs). Results: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m2 ) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m2 ) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of Cmax , AUC0−t , and AUC0−∞ ) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of Cmax , AUC0−t , and AUC0−∞ ) of both atorvastatin (0.73–0.91, 0.92–1.02, and 0.91–1.01, respectively) and ortho-hydroxy-atorvastatin (0.83–1.05, 0.92–1.02, and 0.93–1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug. Conclusions: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512.