Assessment of 2012 Bioequivalence Standards for Warfarin
1 de agosto de 2019 actualizado por: University of California, San Francisco
Assessment of 2012 Bioequivalence Standards for Narrow Therapeutic Index Drugs: a Study With Warfarin
The purpose of this study is to assess the 2012 bioequivalence statistical criteria for warfarin, a narrow therapeutic index drug, set forth in the draft guidance issued by the Food and Drug Administration (FDA).
Descripción general del estudio
Descripción detallada
This study is a reasonable starting point to assess the appropriateness of the 2012 FDA bioequivalence (BE) statistical criteria for narrow therapeutic index drugs (NTIDs). The idea stems from an earlier study conducted in Dr. Benet's lab with the drug furosemide. The furosemide study yielded triplicate data that were unable to purely meet the BE statistical criteria set forth by the FDA due to the inherent study design. Furosemide is not an NTID to be considered by the FDA for BE studies, however. Hence, the investigators have proposed a new study to assess the BE statistical criteria with warfarin, an NTID with a draft guidance issued by the FDA. By providing the reference product (brand name warfarin) three times to each study participant and recording the relevant pharmacokinetic parameters for BE (AUC and Cmax), the investigators can make three comparisons between the data (R1 and R2 vs. R2 and R3; R1 and R2 vs. R1 and R¬3; R2 and R3 vs. R1 and R3).
The investigators have three concerns that can be tested here.
- Will normal within subject variability potentially lead to inequivalence of the reference product using the new NTID BE regulations?
- Is it possible that the BE interval could be less than the United States Pharmacopeia (USP) content uniformity limits for warfarin?
- Provide a comparison of the within-subject variance for the 2.5 ratio comparison.
Tipo de estudio
Intervencionista
Inscripción (Actual)
10
Fase
- Fase 1
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
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California
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San Francisco, California, Estados Unidos, 94143
- University of California, San Francisco
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Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Edades elegibles para estudiar
18 años a 60 años (Adulto)
Acepta Voluntarios Saludables
Sí
Géneros elegibles para el estudio
Todos
Descripción
Inclusion Criteria:
- Male or female aged 18-60 years
- Healthy adult without active medical problems or chronic diseases based on medical history, physical exam, and laboratory results
- BMI 18.5-32 kg/m2
- Ceased all medications 2 weeks prior to start of study and during study enrollment (includes drugs of abuse, prescription medications, and over-the-counter (OTC) medications [exception: acetaminophen])
- Maintain adequate birth control independent of hormonal contraceptive use throughout study
- Provide written informed consent to take part in and comply with the requirements of the study
- Speak, read, and understand English
- Avoid alcohol, caffeine, and orange juice from 6pm the night before the study day until the completion of the study day
- Avoid contact sports and/or other activities with significant risk of trauma injury for 7 days after each study day
- Do not eat food or consume beverages at least 8 hours before medication dosing
- Present with wild type VKORC1, VKORC-1639G>A and wild type CYP2C9 genotype
Exclusion Criteria:
- Subjects on prescription or chronic OTC medications (including hormonal contraceptives)
- Subjects with known allergy to warfarin
- Subjects with a history of or diagnosis of hemorrhagic tendencies or blood dyscrasias
- Subjects with liver failure or liver function tests (LFTs) > 2x upper limit normal
- Subjects with clinically significant elevations of international normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), serum creatinine (Scr), blood urea nitrogen (BUN), or other screening laboratory tests as determined by study physician
- Subjects with hematocrit (Hct) < 30 mg/dL
- Subjects with history of GI bleed or peptic ulcer disease
- Subjects with recent history of trauma
- Subjects with recent history of or upcoming plan for surgery
- Subjects who smoke tobacco
- Subjects with ongoing alcohol use
- Subjects with ongoing illegal drug use
- Subjects who are pregnant, attempting to become pregnant, or lactating
- Subjects who are unable to maintain adequate birth control during the study
- Subjects who are unable to follow protocol instructions or criteria
- Subjects with genotypes that are not wild type VKORC1, VKORC-1639G>A and wild type CYP2C9
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Ciencia básica
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Experimental: warfarin
Subjects will receive a single dose of warfarin 10 mg PO at each of 3 visits.
The study days will be separated by at least 14 days to allow adequate time for the drug to reach washout.
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warfarin 10 mg PO x 1
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-Time Curve (AUC) from 0 to 72 hours
Periodo de tiempo: 0 to 72 hours after warfarin dosing
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The primary outcome measure will be warfarin area-under-the-concentration-time curve (AUC) values from zero to seventy-two (0-72) hours.
Values from the Experimental Arm (warfarin) of each the 3 study periods will be compared against each other and analyzed for intra-individual variability and tested for bioequivalence using the new narrow therapeutic index drug (NTID) regulations.
Blood collection at 0, 1, 2, 3, 4, 6, 8, 12 hours after warfarin dosing.
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0 to 72 hours after warfarin dosing
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) from time zero to infinity hours
Periodo de tiempo: 0 to 8 weeks after warfarin dosing
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A secondary outcome measure will be warfarin area-under-the-concentration-time curve (AUC) values from zero to infinite time (0-inf) where infinite time represents the duration of the study (8 weeks).
Values from the Experimental Arm (warfarin) of each the 3 study periods will be compared against each other and analyzed for intra-individual variability and tested for bioequivalence using the new narrow therapeutic index drug (NTID) regulations.
Analysis of all concentration-time data; blood collection at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours after warfarin dosing.
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0 to 8 weeks after warfarin dosing
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Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin
Periodo de tiempo: 0 to 72 hours after warfarin dosing
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A secondary outcome measure will be maximum plasma concentration (Cmax).
Values from the Experimental Arm (warfarin) of each the 3 study periods will be compared against each other and analyzed for intra-individual variability and tested for bioequivalence using the new narrow therapeutic index drug (NTID) regulations.
Blood collection 0, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after warfarin dosing.
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0 to 72 hours after warfarin dosing
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Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Investigadores
- Investigador principal: Leslie Z Benet, PhD, University of California, San Francisco
- Investigador principal: Lynda A Frassetto, MD, University of California, San Francisco
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio
1 de mayo de 2016
Finalización primaria (Actual)
1 de febrero de 2019
Finalización del estudio (Actual)
1 de febrero de 2019
Fechas de registro del estudio
Enviado por primera vez
9 de septiembre de 2015
Primero enviado que cumplió con los criterios de control de calidad
9 de octubre de 2015
Publicado por primera vez (Estimar)
14 de octubre de 2015
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
5 de agosto de 2019
Última actualización enviada que cumplió con los criterios de control de calidad
1 de agosto de 2019
Última verificación
1 de agosto de 2019
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- 15-17226
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .
Ensayos clínicos sobre warfarin
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