Comparison of dissolution profiles: 90% confidence intervals of different f estimators using bootstrap methodology versus the Euclidean Distance of the Non-standardized Expected (EDNE) values.

The most widely used method to compare dissolution profiles is the similarity factor f method. When the regulatory requirements to apply the f method are not fulfilled, alternative methods should be used. In the current study two commonly used methods, 90% confidence intervals (CI) of different f estimators using bootstrap methodology and the Euclidean Distance of the Non-standardized Expected (EDNE) values, are compared using two different simulation approaches.

A physiologically based pharmacokinetic model to describe [Zr]Zr-DFO-Adalimumab specific activity after intravitreal administration to rats with endotoxin-induced uveitis.

Despite new biologic drugs have been developed to change the course of ocular disorders, the delivery and quantification of drug exposure in the eye remains as a critical challenge. This work aimed to develop a physiologically based pharmacokinetic (PBPK) model of [Zr]Zr-DFO-Adalimumab after intravitreal (IVT) administration in healthy and endotoxin-induced uveitis (EIU) diseased rats to assess the effect of dose on TNF-α reduction in the anterior chamber of the eye. A full PBPK model considering both eyes and cervical lymph nodes was created in PK-Sim®/MoBi®.

Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment.

: Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications (i.e., physiologically based biopharmaceutics modeling (PBBM)) enables mechanistic modeling from dissolution to absorption and disposition, facilitating the prediction of bioequivalence (BE) outcomes and the delimitation of the safe space.

Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs.

Introduction And Objective: Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data.

Methods: A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium.

Personalized Secukinumab Treatment in Patients with Plaque Psoriasis Using Model-Informed Precision Dosing.

Patient care and control of inflammatory disorders, such as psoriasis, can be improved by model-informed precision dosing (MIPD) techniques based on population pharmacokinetic/pharmacodynamic (PK/PD) models. Clinical dose selection decisions based on MIPD strategies need to take account of the uncertainty associated with the individual PK/PD model parameters, which is determined by the quantity of individual observational data collected in clinical practice. The aim of this study was to propose an approach for personalized dosage regimens of secukinumab (SCK) in 22 Spanish patients with plaque psoriasis, whose severity level was considered moderate to severe, taking into account the uncertainty associated with individual parameters in a population-based PK/PD model.

Artificial Intelligence and Machine Learning Applications to Pharmacokinetic Modeling and Dose Prediction of Antibiotics: A Scoping Review.

The use of artificial intelligence (AI) and, in particular, machine learning (ML) techniques is growing rapidly in the healthcare field. Their application in pharmacokinetics is of potential interest due to the need to relate enormous amounts of data and to the more efficient development of new predictive dose models. The development of pharmacokinetic models based on these techniques simplifies the process, reduces time, and allows more factors to be considered than with classical methods, and is therefore of special interest in the pharmacokinetic monitoring of antibiotics.

Model-Informed Precision Dosing for Personalized Ustekinumab Treatment in Plaque Psoriasis.

Background/objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting clinical dose selection decisions.

Methods: This study proposes a methodology to individualize ustekinumab (UTK) dosing strategies for 23 Spanish patients with moderate to severe chronic plaque psoriasis.

Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs).

Impact of Time on Parameters for Assessing the Microstructure Equivalence of Topical Products: Diclofenac 1% Emulsion as a Case Study.

The demonstration of bioequivalence proposed in the European Medicines Agency's (EMA's) draft guideline for topical products with the same qualitative and quantitative composition requires the confirmation of the internal structure equivalence. The impact of the shelf-life on the parameters proposed for internal structure comparison has not been studied. The objectives of this work were: (1) to quantify the effect of the time since manufacturing on the mean value and variability of the parameters proposed by the EMA to characterize the internal structure and performance of topical formulations of a complex topical formulation, and (2) to evaluate the impact of these changes on the assessment of the microstructure equivalence.

Bioequivalence risk assessment of oral formulations containing racemic ibuprofen through a chiral physiologically based pharmacokinetic model of ibuprofen enantiomers.

The characterization of the time course of ibuprofen enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence studies. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents the most efficient methodology to virtually assess bioequivalence outcomes. In this work, we aim to develop and verify a PBPK model for ibuprofen enantiomers administered as a racemic mixture with different immediate release dosage forms to anticipate bioequivalence outcomes based on different particle size distributions.

Towards precision medicine of long-acting aripiprazole through population pharmacokinetic modelling.

Population pharmacokinetic (popPK) models constitute a valuable tool for characterizing the pharmacokinetic properties of once-monthly long-acting injectable aripiprazole (LAI aripiprazole) and quantifying the sources of variability in drug exposure. Our aim is to develop a popPK model of both aripiprazole and its metabolite dehydro-aripiprazole in patients treated with LAI aripiprazole, and to personalize the dosing regimen of aripiprazole across different sub-groups of patients. This is a prospective study investigating the pharmacokinetics of LAI aripiprazole.

New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model.

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients.

Phys-DAT: A physiologically-based pharmacokinetic model for unraveling the dissolution, transit and absorption processes using PhysPK®.

Background And Objective: In silico methods have become the key for efficiently testing and qualifying drug properties. Due to the complexity of the LADME processes and drug characteristics associated to oral drug absorption, there is a growing demand in the development of Physiologically-based Pharmacokinetic (PBPK) software with greater flexibility. Thus, the aims of this work are (i) to develop a mechanistic-based modeling framework of dissolution, transit and absorption (Phys-DAT) processes in the PhysPK platform and (ii) to assess the predictive power of the acausal MOOM methodology embedded in Phys-DAT versus reference ODE-based PBPK software.

Usage of model combination in computational toxicology.

New Approach Methodologies (NAMs) have ushered in a new era in the field of toxicology, aiming to replace animal testing. However, despite these advancements, they are not exempt from the inherent complexities associated with the study's endpoint. In this review, we have identified three major groups of complexities: mechanistic, chemical space, and methodological.

Mechanistic characterization of oscillatory patterns in unperturbed tumor growth dynamics: The interplay between cancer cells and components of tumor microenvironment.

Mathematical modeling of unperturbed and perturbed tumor growth dynamics (TGD) in preclinical experiments provides an opportunity to establish translational frameworks. The most commonly used unperturbed tumor growth models (i.e.

Integrating Mechanistic and Toxicokinetic Information in Predictive Models of Cholestasis.

Drug development involves the thorough assessment of the candidate's safety and efficacy. toxicology (IST) methods can contribute to the assessment, complementing and experimental methods, since they have many advantages in terms of cost and time. Also, they are less demanding concerning the requirements of product and experimental animals.

Application of population physiologically based pharmacokinetic modelling to optimize target expression and clearance mechanisms of therapeutic monoclonal antibodies.

Aims: To use population physiologically based pharmacokinetic (PopPBPK) modelling to optimize target expression, kinetics and clearance of HER1/2 directed therapeutic monoclonal antibodies (mAbs). Thus, to propose a general workflow of PopPBPK modelling and its application in clinical pharmacology.

Methods: Full PBPK model of pertuzumab (PTZ) was developed in patient population using Simcyp V21R1 incorporating mechanistic targeted-mediated drug disposition process by fitting known clinical PK and sparse receptor proteomics data to optimize target expression and kinetics of HER2 receptor.

Regulatory Requirements for the Development of Second-Entry Semisolid Topical Products in the European Union.

The development of second-entry topical products is hampered by several factors. The excipient composition should be similar to the reference product because excipients may also contribute to efficacy. Conventional pharmacokinetic bioequivalence studies were not considered acceptable because drug concentrations are measured downstream after the site of action.

Alternative Pharmacokinetic Metrics in Single-Dose Studies to Ensure Bioequivalence of Prolonged-Release Products at Steady State-A Case Study.

(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, C, partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for C, AUC and AUC, in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (C, AUC and AUC) and additional (C, pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC, C, and C) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration-time curves precluded to show equivalence for C in the simulated study at steady state.

A physiologically based pharmacokinetic model for open acid and lactone forms of atorvastatin and metabolites to assess the drug-gene interaction with SLCO1B1 polymorphisms.

Atorvastatin is the most prescribed 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used to lower cardiovascular risk and constitutes one of the best-selling drugs world-wide. Several physiologically based pharmacokinetic (PBPK) models have been developed to assess its non-straightforward pharmacokinetics (PK) as well as that of its metabolites and have been only applied to assess drug-drug interactions (DDI). Here we present a full PBPK model for atorvastatin and its metabolites able to predict within a 2-fold error their PK after the administration of a solid oral dosage form containing the calcium salt of atorvastatin in single and multiple dosing schedules at 20, 40, and 80 mg and 10 mg dose levels, respectively.

Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment.

The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. Several structural PK models including linear and non-linear binding kinetics were evaluated. Monte Carlo simulations were conducted with a fixed combination of creatinine clearance (30-90 mL/min/1.