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 an...
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

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 i...
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

Comparing the performance of first-order conditional estimation (FOCE) and different expectation –maximization (EM) methods in NONMEM: real data experience with complex nonlinear parent-metabolite pharmacokinetic model
In this study, we compared the performance of FOCE, FOCE FAST, and two EM methods, namely importance sampling (IMP) and stochastic approximation expectation–maximization (SAEM), utilizing the rich pharma cokinetic data of oxfendazole and its two metabolites obtained from the first-in-human single ascending dose study in healthy adults. All methods yielded similar parameter estimates, but great differences were observed in parameter precision and modeling time. For simpler models (i.e., models of oxf endazole and/or oxfendazole sulfone), FOCE and FOCE FAST were more efficient than EM methods with shorter run time and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Constant infusion case of one compartment pharmacokinetic model with simultaneous first-order and Michaelis –Menten elimination: analytical solution and drug exposure formula
AbstractThe main objective of this article is to propose the closed-form solution of one-compartment pharmacokinetic model with simultaneous first-order and Michaelis –Menten elimination for the case of constant infusion. For the case of bolus administration, we have previously established a closed-form solution of the model through introducing a transcendentX function. In the same vein, we found here a closed-form solution of constant infusion could be realized through introducing another transcendentY function. For the general case of constant infusion of limited duration, the closed-form solution is then fully exp...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Fast screening of covariates in population models empowered by machine learning
AbstractOne of the objectives of Pharmacometry (PMX) population modeling is the identification of significant and clinically relevant relationships between parameters and covariates. Here, we demonstrate how this complex selection task could benefit from supervised learning algorithms using importance scores. We compare various classical methods with three machine learning (ML) methods applied to NONMEM empirical Bayes estimates: random forest, neural networks (NNs), and support vector regression (SVR). The performance of the ML models is assessed using receiver operating characteristic (ROC) curves. The F1 score, which me...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody
AbstractThe thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modellin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

A semi-mechanistic exposure –response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases
AbstractVerinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure –response model for uric acid kinetics to include between-subject variability to verinurad and its co...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Reduction of quantitative systems pharmacology models using artificial neural networks
In this study, we explore the use of artificial neural networks for approximating an input–output relationship within highly dimensional systems models. We illustrate this approach using a model of blood coagulation. The model consists of two components linked together thro ugh a highly dimensional discontinuous interface, which creates a difficulty for model reduction techniques. The proposed approach enables the development of an efficient approximation to complex models with the desired level of accuracy. The technique is applicable to a wide variety of models and p rovides substantial speed boost for use of such ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.
AbstractPredictions for target engagement are often used to guide drug development. In particular, when selecting the recommended phase 2 dose of a drug that is very safe, and where good biomarkers for response may not exist (e.g. in immuno-oncology), a receptor occupancy prediction could even be the main determinant in justifying the approved dose, as was the case for atezolizumab. The underlying assumption in these models is that when the drug binds its target, it disrupts the interaction between the target and its endogenous ligand, thereby disrupting downstream signaling. However, the interaction between the target and...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Optimum multi-drug regime for compartment model of tumour: cell-cycle-specific dynamics in the presence of resistance
The objective is to determine the optimal drug schedule according to the patient ’s physiological condition so that the tumour burden is minimised. A multi-objective optimisation algorithm, non-dominated sorting genetic algorithm-II (NSGA-II) is utilised to solve the problem. The obtained results are thoroughly analysed to illustrate the impact of drug resistance on the treatm ent. The capability of optimised schedules to deal with parametric uncertainty is also analysed. The drug schedules obtained in this work align well with the clinical standards. It is also revealed that the NSGA-II optimised drug schedule with ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy
AbstractIntermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in act...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic characteristics of cemiplimab in patients with advanced malignancies
AbstractCemiplimab, a human monoclonal antibody targeting programmed cell death-1 (PD-1) receptor, demonstrated antitumor activity in patients with advanced malignancies and a safety profile comparable to other anti –PD-1 therapies. This population pharmacokinetics (PopPK) analysis of cemiplimab included 11,178 pharmacokinetics (PK) observations from 548 patients pooled from a first-in-human study (Study 1423; NCT02383212) in advanced malignancies and a Phase 2 study (Study 1540; NCT02760498) in advanced cuta neous squamous cell carcinoma (CSCC). Most patients (80.3%) received cemiplimab 3 mg/kg every 2 wee...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Modeling the acute effects of exercise on glucose dynamics in healthy nondiabetic subjects
A correction to this paper has been published: https://doi.org/10.1007/s10928-021-09766-9 (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9)
A correction to this paper has been published: https://doi.org/10.1007/s10928-021-09767-8 (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2021 Category: Drugs & Pharmacology Source Type: research

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149
We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies. The mathematical expression was derived from a pharmacokinetic model that assumes the existence of a compartment between the vitreous humor compartment itself and the systemic compartment. We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye ha...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Delay differential equations based models in NONMEM
AbstractDelay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time. Two of them are based on algorithms already applied elsewhere, while others are extensions of existing ordinary differential equations (ODEs) solvers. The purpose of this tutorial is to introduce basic concepts underlying DDE based models and to  show how they can be developed using NONMEM. The examples include previously published DDE models such as logistic growth, tumor growt...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687
We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149
We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies. The mathematical expression was derived from a pharmacokinetic model that assumes the existence of a compartment between the vitreous humor compartment itself and the systemic compartment. We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye ha...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Delay differential equations based models in NONMEM
AbstractDelay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time. Two of them are based on algorithms already applied elsewhere, while others are extensions of existing ordinary differential equations (ODEs) solvers. The purpose of this tutorial is to introduce basic concepts underlying DDE based models and to  show how they can be developed using NONMEM. The examples include previously published DDE models such as logistic growth, tumor growt...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687
We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Linking categorical models for prediction of pleasantness score using individual predictions of sweetness and creaminess: An advancement of categorical modeling
AbstractThe aim of this work was to develop and evaluate approaches of linked categorical models using individual predictions of probability. A model was developed using data from a study which assessed the perception of sweetness, creaminess, and pleasantness in dairy solutions containing variable concentrations of sugar and fat. Ordered categorical models were used to predict the individual sweetness and creaminess scores and these individual predictions were used as covariates in the model of pleasantness response. The model using individual predictions was compared to a previously developed model using the amount of fa...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 1, 2021 Category: Drugs & Pharmacology Source Type: research

Optimal control for colistin dosage selection
This study formulates an optimal control problem for dosage selection of colistin based on a PK model, minimizing deviations of colistin concentration to a target value and allowing a specific dosage optimization for a given individual. An adjoint model was used to provide the sensitivity of concentration deviations to dose changes. A three-compartment PK model was adopted. The standard deviation between colistin plasma concentrations and a target set at 2  mg/L was minimized for some chosen treatments and sample patients. Significantly lower deviations from the target concentration are obtained for shorter administra...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 22, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacometric estimation methods for aggregate data, including data simulated from other pharmacometric models
AbstractLack of data is an obvious limitation to what can be modelled. However, aggregate data in the form of means and possibly (co)variances, as well as previously published pharmacometric models, are often available. Being able to use all available data is desirable, and therefore this paper will outline several methods for using aggregate data as the basis of parameter estimation. The presented methods can be used for estimation of parameters from aggregate data, and as a computationally efficient alternative for the stochastic simulation and estimation procedure. They also allow for population PK/PD optimal design in ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 22, 2021 Category: Drugs & Pharmacology Source Type: research

Optimal control for colistin dosage selection
This study formulates an optimal control problem for dosage selection of colistin based on a PK model, minimizing deviations of colistin concentration to a target value and allowing a specific dosage optimization for a given individual. An adjoint model was used to provide the sensitivity of concentration deviations to dose changes. A three-compartment PK model was adopted. The standard deviation between colistin plasma concentrations and a target set at 2  mg/L was minimized for some chosen treatments and sample patients. Significantly lower deviations from the target concentration are obtained for shorter administra...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 22, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacometric estimation methods for aggregate data, including data simulated from other pharmacometric models
AbstractLack of data is an obvious limitation to what can be modelled. However, aggregate data in the form of means and possibly (co)variances, as well as previously published pharmacometric models, are often available. Being able to use all available data is desirable, and therefore this paper will outline several methods for using aggregate data as the basis of parameter estimation. The presented methods can be used for estimation of parameters from aggregate data, and as a computationally efficient alternative for the stochastic simulation and estimation procedure. They also allow for population PK/PD optimal design in ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 22, 2021 Category: Drugs & Pharmacology Source Type: research

Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice
AbstractIn the past, our lab proposed a two-pore PBPK model for different-size protein therapeutics using de novo derived parameters and the model was validated using plasma PK data of different-size antibody fragments digitized from the literature (Li Z, Shah DK, J Pharmacokinet Pharmacodynam 46(3):305 –318, 2009). To further validate the model using tissue distribution data, whole-body biodistribution study of 6 different-size proteins in mice were conducted. Studied molecules covered a wide MW range (13–150 kDa). Plasma PK and tissue distribution profiles is 9 tissues were measured, includi ng heart, ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 19, 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 - June 17, 2021 Category: Drugs & Pharmacology Source Type: research

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 i...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 11, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9)
A correction to this paper has been published: https://doi.org/10.1007/s10928-021-09767-8 (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 11, 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 an...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 7, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Modeling the acute effects of exercise on glucose dynamics in healthy nondiabetic subjects
A correction to this paper has been published: https://doi.org/10.1007/s10928-021-09766-9 (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 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 - May 25, 2021 Category: Drugs & Pharmacology Source Type: research

Fast screening of covariates in population models empowered by machine learning
AbstractOne of the objectives of Pharmacometry (PMX) population modeling is the identification of significant and clinically relevant relationships between parameters and covariates. Here, we demonstrate how this complex selection task could benefit from supervised learning algorithms using importance scores. We compare various classical methods with three machine learning (ML) methods applied to NONMEM empirical Bayes estimates: random forest, neural networks (NNs), and support vector regression (SVR). The performance of the ML models is assessed using receiver operating characteristic (ROC) curves. The F1 score, which me...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 21, 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 - May 19, 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 - May 15, 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 - May 12, 2021 Category: Drugs & Pharmacology Source Type: research