RESUMEN
Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index [BMI] = 20) and subjects with various severities of obesity (BMI 25-60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m2, in any of the other cases, information on the different drug properties and severity of obesity is required to select an appropriate dosing method for individuals with obesity.
Asunto(s)
Índice de Masa Corporal , Modelos Biológicos , Obesidad , Humanos , Obesidad/metabolismo , Tasa de Depuración Metabólica/fisiología , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Hígado/metabolismo , Orosomucoide/metabolismo , Albúmina Sérica Humana/metabolismo , Albúmina Sérica Humana/análisis , Masculino , AdultoRESUMEN
Population pharmacokinetic analysis is used to estimate pharmacokinetic parameters and their variability from concentration data. Due to data sparseness issues, available datasets often do not allow the estimation of all parameters of the suitable model. The PRIOR subroutine in NONMEM supports the estimation of some or all parameters with values from previous models, as an alternative to fixing them or adding data to the dataset. From a literature review, the best practices were compiled to provide a practical guidance for the use of the PRIOR subroutine in NONMEM. Thirty-three articles reported the use of the PRIOR subroutine in NONMEM, mostly in special populations. This approach allowed fast, stable and satisfying modelling. The guidance provides general advice on how to select the most appropriate reference model when there are several previous models available, and to implement and weight the selected parameter values in the PRIOR function. On the model built with PRIOR, the similarity of estimates with the ones of the reference model and the sensitivity of the model to the PRIOR values should be checked. Covariates could be implemented a priori (from the reference model) or a posteriori, only on parameters estimated without prior (search for new covariates).
Asunto(s)
Variación Biológica Poblacional , Simulación por Computador/normas , Modelos Biológicos , Farmacología Clínica/normas , Guías de Práctica Clínica como Asunto , Teorema de Bayes , Conjuntos de Datos como Asunto , Humanos , Cadenas de Markov , Farmacología Clínica/métodos , Programas InformáticosRESUMEN
Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1-17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Modelos Biológicos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Citrato de Sildenafil/farmacocinéticaRESUMEN
Although children cannot be considered small adults due to nonlinear processes underlying the pharmacokinetics of drugs, pediatric doses are typically still expressed per kilogram. We use a physiologically based pharmacokinetic (PBPK) workflow to assess the accuracy of linear scaling of plasma clearance (CLp) for hypothetical drugs with ranges of realistic parameter values in pediatric patients of different ages. The results are compared with 0.75 fixed allometric scaling (AS 0.75). Linear CLp scaling is accurate down to the age of 1 month for drugs undergoing glomerular filtration, except when these drugs are highly bound to alpha-1-acid glycoprotein (AGP). For hepatically cleared drugs, linear scaling is reasonably accurate down the age of 2 years, except for AGP-bound drugs with a low extraction ratio and mature isoenzymes. In neonates, linear scaling outperforms AS 0.75 for human serum albumin (HSA) and AGP-bound drugs excreted through glomerular filtration. These results suggest that pediatric patients can, in many cases, be treated as small adults.
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Hígado/metabolismo , Orosomucoide/metabolismo , Albúmina Sérica Humana/metabolismo , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Tasa de Depuración Metabólica , Modelos Biológicos , Modelos Teóricos , Flujo de Trabajo , Adulto JovenRESUMEN
In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CLpop) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CLpop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CLpop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CLpop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CLpop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CLTV) at a relevant weight to evaluate the precision of CL predictions.
Asunto(s)
Peso Corporal , Modelos Biológicos , Farmacocinética , Adulto , Humanos , Recién Nacido , Obesidad/metabolismo , Fenobarbital/farmacocinéticaRESUMEN
PURPOSE: Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint,u,WL) and hepatic blood flow (Qh) in children. METHODS: First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual variability were established using a novel application of population optimal design theory. Finally, the performance of the proposed trial design was assessed using stochastic simulation and estimation. RESULTS: Precise estimation of CLint,u,WL and Qh and their inter-individual variability was found to require a trial with two drugs, of which one has an extraction ratio (ER) ≤ 0.27 and the other has an ER ≥ 0.93. The proposed clinical trial design was found to lead to precise and accurate parameter estimates and was robust to parameter uncertainty. CONCLUSION: The proposed framework can be applied to other PBPK parameters and facilitate the development of PBPK models.
Asunto(s)
Simulación por Computador , Descubrimiento de Drogas/métodos , Hígado/metabolismo , Tasa de Depuración Metabólica , Modelos Biológicos , Niño , Ensayos Clínicos como Asunto , Humanos , Cinética , Hígado/irrigación sanguínea , Distribución Tisular , IncertidumbreRESUMEN
For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month.
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Isoenzimas/metabolismo , Hígado/metabolismo , Preparaciones Farmacéuticas/análisis , Niño , Preescolar , Cálculo de Dosificación de Drogas , Eliminación Hepatobiliar , Humanos , Lactante , Tasa de Depuración Metabólica , Modelos Biológicos , FarmacocinéticaRESUMEN
Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of 'true' paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated 'true' paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on 'true' CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age.
Asunto(s)
Peso Corporal/fisiología , Modelos Biológicos , Preparaciones Farmacéuticas/sangre , Adolescente , Peso Corporal/efectos de los fármacos , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/fisiología , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
OBJECTIVE: To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome. DESIGN: Prospective, single-center observational trial. SETTING: PICU in a university-affiliated pediatric teaching hospital. PATIENTS: Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis. MEASUREMENTS AND MAIN RESULTS: Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 µg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 µg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome. CONCLUSIONS: This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome.
Asunto(s)
Analgésicos Opioides/farmacocinética , Procedimientos Quirúrgicos Cardíacos , Síndrome de Down/cirugía , Morfina/farmacocinética , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos Opioides/sangre , Analgésicos Opioides/uso terapéutico , Estudios de Casos y Controles , Preescolar , Cuidados Críticos/métodos , Síndrome de Down/sangre , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Morfina/sangre , Morfina/uso terapéutico , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Cuidados Posoperatorios/métodos , Estudios Prospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of varying ages may be anticipated, due to developmental changes occurring across pediatric life. AREAS COVERED: Beside pharmacokinetic (PK) studies, pharmacodynamic (PD) studies are urgently needed. Validated PKPD models can be used to derive optimal dosing regimens for children of different ages, which can be evaluated in a prospective study before implementation in clinical practice. Strategies should be developed to ensure that formularies update their drug dosing guidelines regularly according to the most recent advances in research, allowing for clinicians to integrate these guidelines in daily practice. Expert commentary: We anticipate a trend towards a systems-level approach in pediatric modeling to optimally use the information gained in pediatric trials. For this approach, properly designed clinical PKPD studies will remain the backbone of pediatric research.