PMID- 19843490
OWN - NLM
STAT- MEDLINE
DCOM- 20100118
LR  - 20131121
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 31
IP  - 9
DP  - 2009 Sep
TI  - A single-dose, three-period, six-sequence crossover study comparing the 
      bioavailability of solution, suspension, and enteric-coated tablets of magnesium 
      valproate in healthy Mexican volunteers under fasting conditions.
PG  - 2002-11
LID - 10.1016/j.clinthera.2009.09.016 [doi]
AB  - BACKGROUND: Valproic acid has been associated with a highly variable intersubject 
      absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was 
      developed to diminish variation during enteric absorption. OBJECTIVES: The aims 
      of this study were to assess the pharmacokinetics of single oral doses of MgV 
      500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican 
      population, and to compare formulation-related differences. METHODS: This was a 
      randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican 
      volunteers aged 18 to 45 years. In each period, subjects received single oral 
      doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, 
      with a 7-day washout period between each dosing period. Serial blood samples were 
      collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 
      3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a 
      new method of ultraperformance liquid chromatography coupled with mass 
      spectrometry. Pharmacokinetic parameters of interest were C(max), T(max), 
      AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and mean residence time (MRT). 
      Formulation-related differences were assayed in accordance with the Mexican 
      regulatory bioequivalence criteria. Log-transformed values of C(max) and AUC were 
      used to construct a classic 90% CI. Bioequivalence was established if the 90% CI 
      for the mean test:reference ratio of log-transformed C(max) and AUC were within 
      the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, 
      vital sign monitoring, and clinical assessment. RESULTS: A total of 24 healthy 
      volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 
      [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m(2)) 
      were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of 
      C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 
      59.75 (8.24) microg/mL, 0.542 (0.14) hours, 1099.67 (241.70) microg h/mL, 1156.30 
      (264.01) microg h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) 
      mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) 
      pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), 
      V(d)/F, CL/F, and MRT were 55.04 (7.72) microg/mL, 0.773 (0.51) hour, 1057.76 
      (223.37) microg h/mL, 1111.09 (245.07) microg h/mL, 16.32 (2.20) hours, 1069.05 
      (1775.64) mL, 435.43 (99.59) mL/h, and 18.41 (1.43) hours, respectively. For the 
      MgV enteric-coated tablets, the mean (SD) pharmacokinetic parameters of C(max), 
      T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 54.88 
      (6.73) microg/mL, 2.79 (0.89) hours, 1100.79 (216.70) microg h/mL, 1163.61 
      (238.36) microg h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) 
      mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution 
      ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C(max), 
      AUC(0-72), and AUC(0-infinity), respectively. The 90% CIs for the 
      suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 
      98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 
      104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively. CONCLUSION: This 
      single-dose study found that the 3 formulations (solution, suspension, and 
      enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in 
      these healthy, fasting, Mexican volunteers.
FAU - Marcelin-Jimenez, Gabriel
AU  - Marcelin-Jimenez G
AD  - Clinical Pharmacology Research Center, Hospital General de Mexico, Mexico City, 
      Mexico. gabmarcelin@hotmail.com
FAU - Angeles-Moreno, Alionka P
AU  - Angeles-Moreno AP
FAU - Contreras-Zavala, Leticia
AU  - Contreras-Zavala L
FAU - Morales-Martinez, Miriam
AU  - Morales-Martinez M
FAU - Rivera-Espinosa, Liliana
AU  - Rivera-Espinosa L
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Anticonvulsants)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Pharmaceutical Solutions)
RN  - 0 (Suspensions)
RN  - 0 (Tablets)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Anticonvulsants/administration & dosage/adverse effects/*pharmacokinetics
MH  - Area Under Curve
MH  - Biological Availability
MH  - Chromatography, Liquid/methods
MH  - Cross-Over Studies
MH  - Delayed-Action Preparations
MH  - Female
MH  - Half-Life
MH  - Humans
MH  - Male
MH  - Mass Spectrometry/methods
MH  - Mexico
MH  - Pharmaceutical Solutions
MH  - Suspensions
MH  - Tablets
MH  - Therapeutic Equivalency
MH  - Tissue Distribution
MH  - Valproic Acid/administration & dosage/adverse effects/*pharmacokinetics
MH  - Young Adult
EDAT- 2009/10/22 06:00
MHDA- 2010/01/19 06:00
CRDT- 2009/10/22 06:00
PHST- 2009/08/13 00:00 [accepted]
PHST- 2009/10/22 06:00 [entrez]
PHST- 2009/10/22 06:00 [pubmed]
PHST- 2010/01/19 06:00 [medline]
AID - S0149-2918(09)00345-2 [pii]
AID - 10.1016/j.clinthera.2009.09.016 [doi]
PST - ppublish
SO  - Clin Ther. 2009 Sep;31(9):2002-11. doi: 10.1016/j.clinthera.2009.09.016.