RESUMEN
Physiologically based pharmacokinetic (PBPK) models need the correct organ/tissue weights to match various total body weights in order to be applied to children and the obese individual. Baseline data from Reference Man for the growth of human organs (adrenals, brain, heart, kidneys, liver, lungs, pancreas, spleen, thymus, and thyroid) were augmented with autopsy data to extend the describing polynomials to include the morbidly obese individual (up to 250 kg). Additional literature data similarly extends the growth curves for blood volume, muscle, skin, and adipose tissue. Collectively these polynomials were used to calculate blood/organ/tissue weights for males and females from birth to 250 kg, which can be directly used to help parameterize PBPK models. In contrast to other black/white anthropomorphic measurements, the data demonstrated no observable or statistical difference in weights for any organ/tissue between individuals identified as black or white in the autopsy reports.
Asunto(s)
Algoritmos , Autopsia/estadística & datos numéricos , Obesidad/metabolismo , Tamaño de los Órganos/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Población Negra , Composición Corporal/fisiología , Índice de Masa Corporal , Peso Corporal/fisiología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Análisis de Regresión , Población BlancaRESUMEN
A physiologically based pharmacokinetic (PBPK) model and program (called PostNatal) was developed which focuses on postnatal growth. Algorithms defining organ/tissue growth curves from birth through adulthood for male and female humans, dogs, rats, and mice are utilized to calculate the appropriate weight and blood flow for the internal organs/tissues. This Windows based program is actually four linked PBPK models with each PBPK model acting independently or totally integrated with the others through metabolism by first order or Michaelis-Menten kinetics. Data fitting is accomplished by a weighted least square regression algorithm. The model includes linkages for the simulation of pharmacodynamic (PD) effects.
Asunto(s)
Modelos Biológicos , Farmacocinética , Fenómenos Farmacológicos , Programas Informáticos , Algoritmos , Animales , Perros , Femenino , Crecimiento , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Ratones , Dinámicas no Lineales , RatasRESUMEN
A physiologically based pharmacokinetic (PBPK) model and Windows-based program (called PostNatal) was developed that focuses on postnatal growth, from birth through adulthood, using appropriate growth curves for each species and gender. Postnatal growth algorithms relating organs/tissues weights with total body weight for male and female humans, dogs, rats, and mice are an integral part of the software and are utilized to assign the appropriate weight and blood flow for each of 22 organs/tissues for each simulation. Upper limits of body weight were chosen that reflect the available data used to define the algorithms; above these limits a set percent body weight was assigned to all organs/tissues.
Asunto(s)
Crecimiento , Modelos Teóricos , Farmacocinética , Algoritmos , Animales , Perros , Femenino , Humanos , Masculino , Ratones , Ratas , Programas Informáticos , Distribución TisularRESUMEN
A physiologically based pharmacokinetic model was developed for acrylamide (AA) and three of its metabolites: glycidamide (GA) and the glutathione conjugates of acrylamide (AA-GS) and glycidamide (GA-GS). Liver GA-DNA adducts and hemoglobin (Hb) adducts with AA and GA were included as pharmacodynamic components of the model. Serum AA and GA concentrations combined with urinary elimination levels for all four components from male and female mice and rats were simulated from iv and oral administration of 0.1 mg/kg AA or 0.12 mg/kg GA. Adduct formation and decay rates were determined from a 6 week exposure to approximately 1 mg/kg AA in the drinking water and subsequent 6 week nonexposure period. Human urinary excretion data and Hb adduct data were utilized to extrapolate to a human model. The steady-state human liver GA-DNA adduct level from exposure to background levels of AA in the diet was predicted to be between 0.06 and 0.26 adducts per 10(8) nucleotides.
Asunto(s)
Acrilamida/farmacología , Acrilamida/farmacocinética , Algoritmos , Animales , Animales Recién Nacidos , Biotransformación , Peso Corporal/efectos de los fármacos , Dieta , Ingestión de Líquidos/efectos de los fármacos , Compuestos Epoxi/farmacocinética , Compuestos Epoxi/farmacología , Femenino , Humanos , Cinética , Masculino , Ratones , Modelos Biológicos , Ratas , Ratas Endogámicas F344RESUMEN
A workshop was conducted on November 18-19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adult-like in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.