Journal of Pharmacokinetics and Pharmacodynamics 
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This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.Inferring pulmonary exposure based on clinical PK data: accuracy and precision of model-based deconvolution methods
AbstractDetermining and understanding the target-site exposure in clinical studies remains challenging. This is especially true for oral drug inhalation for local treatment, where the target-site is identical to the site of drug absorption, i.e., the lungs. Modeling and simulation based on clinical pharmacokinetic (PK) data may be a valid approach to infer the pulmonary fate of orally inhaled drugs, even without local measurements. In this work, a simulation-estimation study was systematically applied to investigate five published model structures for pulmonary drug absorption. First, these models were compared for structu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 28, 2021 Category: Drugs & Pharmacology Source Type: research
Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study
In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 26, 2021 Category: Drugs & Pharmacology Source Type: research
A Bayesian population physiologically based pharmacokinetic absorption modeling approach to support generic drug development: application to bupropion hydrochloride oral dosage forms
AbstractWe propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extend...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 22, 2021 Category: Drugs & Pharmacology Source Type: research
What should patients do if they miss a dose of medication? A theoretical approach
AbstractMedication adherence is a major problem for patients with chronic diseases that require long term pharmacotherapy. Many unanswered questions surround adherence, including how adherence rates translate into treatment efficacy and how missed doses of medication should be handled. To address these questions, we formulate and analyze a mathematical model of the drug concentration in a patient with imperfect adherence. We find exact formulas for drug concentration statistics, including the mean, the coefficient of variation, and the deviation from perfect adherence. We determine how adherence rates translate into drug c...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 10, 2021 Category: Drugs & Pharmacology Source Type: research
A quantitative systems pharmacology model of hyporesponsiveness to erythropoietin in rats
In this study, we aimed to develop a quantitative systems pharmacology (QSP) model to examine hyporesponsiveness to rHuEPO in rats. Pharmacokinetic (PK) and pharmacodynamic (PD) data after a single intravenous dose of rHuEPO (100 IU/kg) was obtained from a previous study (Yan et al. in Pharm Res, 30:1026–1036, 2013) including rHuEPO plasma concentrations, erythroid precursors counts in femur bone marrow and spleen, reticulocytes (RETs), red blood cells (RBCs), and hemoglobin (HGB) in circulation. Parameter values were ob tained from literature or calibrated with experimental data. Global sensitivity analysis and model-...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research
A latent variable approach to account for correlated inputs in global sensitivity analysis
AbstractIn drug development decision-making is often supported through model-based methods, such as physiologically-based pharmacokinetics (PBPK). Global sensitivity analysis (GSA) is gaining use for quality assessment of model-informed inference. However, the inclusion and interpretation of correlated factors in GSA has proven an issue. Here we developed and evaluated a latent variable approach for dealing with correlated factors in GSA. An approach was developed that describes the correlation between two model inputs through the causal relationship of three independent factors: the latent variable and the unique variance...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research
A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration
The objective of this work is to advance fundamental understanding of whole-body distribution of IT-administered ASOs. We propos e a physiologically-based pharmacokinetic modeling approach to describe the distribution along the neuroaxis based on PK data from non-human primate (NHP) studies. We aim to understand the key processes that drive and limit ASO access to the CNS target tissues. To elucidate the trade-off between par ameter identifiability and physiological plausibility of the model, several alternative model structures were chosen and fitted to the NHP data. The model analysis of the NHP data led to important qua...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research
Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations
AbstractPredicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predict...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research
A comparison of covariate selection techniques applied to pre-exposure prophylaxis (PrEP) drug concentration data in men and transgender women at risk for HIV
AbstractPre-exposure prophylaxis (PrEP) containing antiretrovirals tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) can reduce the risk of acquiring HIV. Concentrations of intracellular tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) have been used to quantify PrEP adherence; although even under directly observed dosing, unexplained between-subject variation remains. Here, we wish to identify patient-specific factors associated with TFV-DP levels. Data from the iPrEX Open Label Extension (OLE) study were used to compare multiple covariate selection methods for determining demographic an...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research
Concentration-QTc analysis with two or more correlated baselines
In this study, we compared three analysis models through simulations and clinical study examples in settings in which two or more baselines were observed for a subject. We compared a model without baseline adjustment, a model with baseline adjustment, and a model in which baseline and baseline mean were included as covariates. In the simulations and clinical study examples, the model with baseline and baseline mean as covariates demonstrated higher accuracy and power than the other models. This model assumed a specific covariance structure in QTc intervals, which well approximated the correlations between QTc intervals wit...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 1, 2021 Category: Drugs & Pharmacology Source Type: research
