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Título :	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
Creador:	Marcelín Jiménez G
Nivel de acceso:	Open access
Palabras clave :	Anticonvulsivantes - administración & dosificación - Adulto - México Anticonvulsivantes - efectos adversos - Adulto - México Anticonvulsivantes - farmacocinética - Adulto - México Cromatografía Liquida - métodos - Adulto - México Espectrometría de Masas - métodos - Adulto - México Ácido Valproico - administración & dosificación - Adulto - México Ácido Valproico - efectos adversos - Adulto - México Ácido Valproico - farmacocinética - Adulto - México Administración Oral - Adulto - México Suspensiones - Adulto - México Comprimidos Recubiertos - Adulto - México Anticonvulsants - administration & dosage - Adult - Mexico Anticonvulsants - adverse effects - Adult - Mexico Anticonvulsants - pharmacokinetics - Adult - Mexico Chromatography, Liquid - methods - Mexico Mass Spectrometry - methods - Adult - Mexico Valproic Acid - administration & dosage - Adult - Mexico Valproic Acid - adverse effects - Adult - Mexico Valproic Acid - pharmacokinetics - Adult - Mexico Administration, Oral - Adult - Mexico Suspensions - Adult - Mexico Tablets, Enteric-Coated - Adult - Mexico CAS No. 62959-43-7, valproato de magnesio bioavailability, farmacocinética de valproato, Cuantificación de valproato UPLC-MS, anticoagulante lúpico, iones contra, validación cruzada CAS No. 62959-43-7, magnesium valproate bioavailability, valproate pharmacokinetics, UPLC-MS valproate quantitation, anticoagulant counter-ion, cross-validation
Descripción :	Introduction. Recently, the development of technology has reached the availability of neonatal screening (NS) for an increasing number of diseases. In Mexico, the actual official regulation makes obligatory the detection of only one disease -hypothyroidism. Despite this, the regulation has remained without changes since 1988. Panels involved in NS have evolved differently in the Mexican health sector. We undertook this study to determine the variability of the NS panels and the number of detected diseases as well as the diverse methodologies used for their determination in the different institutions of the Mexican health system. Methods. Telephone interviews were made to the directors of the NS program for each federal entity and institution. Results. We found that some institutions only screen for one disease, whereas others screen for up to 60 diseases. Methodology variation was 1 to 5. Conclusions. There is great variability in the number of diseases detected in newborns as well as in the methodologies used. Such inconsistency depends on the place of birth and the parents’ employment for insurance affiliation. This difference leads to unequal opportunities for the detection of severe inherited diseases with high potential of impaired development. It is important to establish equal, fair and modern health policies in regard to NS in Mexico. 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
Colaborador(es) u otros Autores:	Angeles-Moreno AP Contreras-Zavala L Morales-Martínez M Rivera-Espinosa L
Fecha de publicación :	2009
Tipo de publicación:	Artículo
Formato:	pdf
Identificador del Recurso :	10.1016/j.clinthera.2009.09.016
Fuente:	Clin Ther 31(9):2002-11
URI :	http://repositorio.pediatria.gob.mx:8180/handle/20.500.12103/2365
Idioma:	eng
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