Your browser doesn't support javascript.
loading
Demonstrating Contribution of Components of Fixed-Dose Drug Combinations Through Longitudinal Exposure-Response Analysis.
Nøhr-Nielsen, Asbjørn; Lange, Theis; Forman, Julie Lyng; Papathanasiou, Theodoros; Foster, David J R; Upton, Richard N; Bjerrum, Ole Jannik; Lund, Trine Meldgaard.
Afiliación
  • Nøhr-Nielsen A; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Lange T; Copenhagen Centre for Regulatory Science, University of Copenhagen, Copenhagen, Denmark.
  • Forman JL; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
  • Papathanasiou T; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
  • Foster DJR; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Upton RN; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
  • Bjerrum OJ; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
  • Lund TM; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
AAPS J ; 22(2): 32, 2020 01 27.
Article en En | MEDLINE | ID: mdl-31989328
Exposure-response (ER) modeling for fixed-dose combinations (FDC) has previously been found to have an inflated false positive rate (FP), i.e., observing a significant effect of FDC components when no true effect exists. Longitudinal exposure-response (LER) analysis utilizes the time course of the data and is valid for several clinical endpoints for FDCs. The aim of the study was to investigate if LER is applicable for the validation of FDCs by demonstrating the contribution of each component to the overall effect without inflation of FP rates. FP and FN rates associated with ER and LER analysis were investigated using stochastic simulation and estimation. Four hundred thirty-two scenarios with varying numbers of patients, duration, sampling frequency, dose distribution, design, and drug activity were analyzed using a range of linear, log-linear, and non-linear models to asses FP and FN rates. Lastly, the impact of the clinical trial parameters was investigated. LER analyses provided well-controlled FP rates of the expected 5% or less; however, in low information clinical trials consisting of 30 patients, 4 samples, and 20 days, LER analyses lead to inflated FN rates. Parameter investigation showed that when the clinical trial includes sufficient patients, duration, samples, and an appropriate trial design, the FN rates are in general below the expected 5% for LER analysis. Based on the results, LER analysis can be used for the validation of FDCs and fixed ratio drug combinations. The method constitutes a new avenue for providing evidence that demonstrates the contribution of each component to the overall clinical effect.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Farmacocinética / Combinación de Medicamentos / Modelos Biológicos Tipo de estudio: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: AAPS J Asunto de la revista: FARMACOLOGIA / TERAPIA POR MEDICAMENTOS Año: 2020 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Farmacocinética / Combinación de Medicamentos / Modelos Biológicos Tipo de estudio: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: AAPS J Asunto de la revista: FARMACOLOGIA / TERAPIA POR MEDICAMENTOS Año: 2020 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos