PMID- 20678686 OWN - NLM STAT- MEDLINE DCOM- 20101122 LR - 20221207 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 32 IP - 7 DP - 2010 Jul TI - 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. PG - 1396-407 LID - 10.1016/j.clinthera.2010.07.004 [doi] AB - 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 C(max), T(max), t((1/2)), AUC(0-t), and AUC(0-infinity)), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the log transformed ratios of AUC and C(max) of atorvastatin were within the predetermined bioequivalence range (0.80-1.25 for AUC and 0.70-1.43 for C(max)) 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/m(2)) 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/m(2)) 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 C(max), AUC(0-t), and AUC(0-infinity)) 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 C(max), AUC(0-t), and AUC(0-infinity)) 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. CI - 2010 Excerpta Medica Inc. All rights reserved. FAU - Liu, Yan-Mei AU - Liu YM AD - Shanghai Xuhui Central Hospital, China. yanmeiliu25@gmail.com FAU - Pu, Hua-Hua AU - Pu HH FAU - Liu, Gang-Yi AU - Liu GY FAU - Jia, Jing-Ying AU - Jia JY FAU - Weng, Li-Ping AU - Weng LP FAU - Xu, Rong-Jing AU - Xu RJ FAU - Li, Guo-Xiu AU - Li GX FAU - Wang, Wei AU - Wang W FAU - Zhang, Meng-Qi AU - Zhang MQ FAU - Lu, Chuan AU - Lu C FAU - Yu, Chen AU - Yu C LA - eng PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Drugs, Generic) RN - 0 (Heptanoic Acids) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Pyrroles) RN - 0 (Tablets) RN - A0JWA85V8F (Atorvastatin) SB - IM MH - Administration, Oral MH - Adult MH - Area Under Curve MH - Asian People MH - Atorvastatin MH - China MH - Cross-Over Studies MH - Drugs, Generic/administration & dosage/adverse effects/*pharmacokinetics MH - Half-Life MH - Heptanoic Acids/administration & dosage/adverse effects/*pharmacokinetics MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage/adverse effects/*pharmacokinetics MH - Male MH - Pyrroles/administration & dosage/adverse effects/*pharmacokinetics MH - Tablets MH - Therapeutic Equivalency MH - Young Adult EDAT- 2010/08/04 06:00 MHDA- 2010/12/14 06:00 CRDT- 2010/08/04 06:00 PHST- 2010/03/16 00:00 [accepted] PHST- 2010/08/04 06:00 [entrez] PHST- 2010/08/04 06:00 [pubmed] PHST- 2010/12/14 06:00 [medline] AID - S0149-2918(10)00231-6 [pii] AID - 10.1016/j.clinthera.2010.07.004 [doi] PST - ppublish SO - Clin Ther. 2010 Jul;32(7):1396-407. doi: 10.1016/j.clinthera.2010.07.004.