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Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study
AbstractModeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2  years of life is associated with a reduced intelligence quotient between 10 and 14 years. The first goal is to des...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research

Minimal brain PBPK model to support the preclinical and clinical development of antibody therapeutics for CNS diseases
AbstractThere are several antibody therapeutics in preclinical and clinical development, industry-wide, for the treatment of central nervous system (CNS) disorders. Due to the limited permeability of antibodies across brain barriers, the quantitative understanding of antibody exposure in the CNS is important for the design of antibody drug characteristics and determining appropriate dosing regimens. We have developed a minimal physiologically-based pharmacokinetic (mPBPK) model of the brain for antibody therapeutics, which was reduced from an existing multi-species platform brain PBPK model. All non-brain compartments were...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 10, 2021 Category: Drugs & Pharmacology Source Type: research

Evaluation of covariate effects using variance-based global sensitivity analysis in pharmacometrics
AbstractIn pharmacometrics, understanding a covariate effect on an interested outcome is essential for assessing the importance of the covariate. Variance-based global sensitivity analysis (GSA) can simultaneously quantify contribution of each covariate effect to the variability for the interested outcome considering with random effects. The aim of this study was to apply GSA to pharmacometric models to assess covariate effects. Simulations were conducted with pharmacokinetic models to characterize the GSA for assessment of covariate effects and with an example of quantitative systems pharmacology (QSP) models to apply the...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 4, 2021 Category: Drugs & Pharmacology Source Type: research