The quest for balance between capturing data and model complexity: A quantitative clinical pharmacology approach applied to monoclonal antibodies.

The main objective of this tutorial is to provide the readers with a roadmap of how to establish increasingly complex target-mediated drug disposition (TMDD) models for monoclonal antibodies. To this end, we built mathematical models, each with a detailed visualization, starting from the basic TMDD model by Mager and Jusko to the well-established, physiologically based model by Li et al. in a step-wise fashion to highlight the relative importance of key physiological processes that impact mAb kinetics and system dynamics. As the models become more complex, the question of structural and parameter identifiability arises. To address this question, we work through a trastuzumab case example to guide the modeler's choice for model and parameter optimization in light of the context of use. We leave the readers of this tutorial with a brief summary of the advantages and limitations of each model expansion, as well as the model source codes for further self-guided exploration and hands-on analysis.

Evaluating the Clinical Impact of Formulation Variability: A Metoprolol Extended-Release Case Study.

The objective of this research was to evaluate the impact of changes in the formulation of metoprolol extended-release (ER) tablets on dissolution, pharmacokinetic, and exercise-induced heart rate (EIHR) using a combined physiologically based absorption pharmacokinetic, and population pharmacokinetic/pharmacodynamic modeling and simulation approach. Using a previously developed physiologically based absorption pharmacokinetic model in DDDPlus and GastroPlus, we simulated the changes in drug release and exposure as the result of quantitative changes in the release-controlling excipient, hydroxylpropylmethylcellulose, for 50 and 200 mg. The similarity of dissolution profiles was assessed using the f2 test, and bioequivalence was tested on the simulated pharmacokinetic profiles. We used the simulated concentration-time profiles following formulation changes as pharmacokinetic input into a population pharmacokinetic/pharmacodynamic model newly developed in NONMEM to determine if changes in pharmacokinetics lead to clinically significant changes in pharmacodynamics. Pharmacodynamic assessment was based on the percentage reduction in the EIHR from baseline. Therapeutic effect was considered similar when the model-predicted EIHR was within 50% to 85% of the average maximum EIHR of healthy 30-year-old subjects. A 40% or more increase in the release rate constant resulted in dissimilarity in dissolution profiles and bioINequivalence in pharmacokinetics for both 50 and 200 mg. Formulation-related differences in drug release of metoprolol ER tablets can lead to differences in pharmacokinetics. However, the evaluated pharmacokinetic differences do not lead to clinically meaningful differences in EIHR, suggesting that EIHR may not be sensitive enough to detect changes in pharmacokinetics of metoprolol ER products.

Model-Based Approach to Predict Adherence to Protocol During Antiobesity Trials.

Development of antiobesity drugs is continuously challenged by high dropout rates during clinical trials. The objective was to develop a population pharmacodynamic model that describes the temporal changes in body weight, considering disease progression, lifestyle intervention, and drug effects. Markov modeling (MM) was applied for quantification and characterization of responder and nonresponder as key drivers of dropout rates, to ultimately support the clinical trial simulations and the outcome in terms of trial adherence. Subjects (n = 4591) from 6 Contrave® trials were included in this analysis. An indirect-response model developed by van Wart et al was used as a starting point. Inclusion of drug effect was dose driven using a population dose- and time-dependent pharmacodynamic (DTPD) model. Additionally, a population-pharmacokinetic parameter- and data (PPPD)-driven model was developed using the final DTPD model structure and final parameter estimates from a previously developed population pharmacokinetic model based on available Contrave® pharmacokinetic concentrations. Last, MM was developed to predict transition rate probabilities among responder, nonresponder, and dropout states driven by the pharmacodynamic effect resulting from the DTPD or PPPD model. Covariates included in the models and parameters were diabetes mellitus and race. The linked DTPD-MM and PPPD-MM was able to predict transition rates among responder, nonresponder, and dropout states well. The analysis concluded that body-weight change is an important factor influencing dropout rates, and the MM depicted that overall a DTPD model-driven approach provides a reasonable prediction of clinical trial outcome probabilities similar to a pharmacokinetic-driven approach.

Interfacial engineering of pyridinium gemini surfactants for the generation of synthetic transfection systems.

Pyridinium gemini surfactants possess a soft charge, a high charge/mass ratio and a high molecular flexibility - all key parameters that recommend their use in synthetic gene delivery systems with in vitro and in vivo efficiency. In present study we generated a DNA delivery system through interfacial engineering of pyridinium gemini surfactants at the level of linker, hydrophobic chains and counterions. The self-assembling of the pyridinium amphiphiles and the physicochemical properties of the resultant supra-molecular assemblies were studied in bulk and in solution through a combination of techniques that included DSC, X-ray diffraction, polarized microscopy, CMC, dynamic light scattering and zeta potential measurements. We assessed the impact of different structural elements and formulation parameters of these pyridinium amphiphiles on their DNA compaction properties, transfection efficiency, cytotoxicity, in a complete structure-activity relationship study. This interfacial engineering process generated transfection systems with reduced cytotoxicity and high transfection efficiency in media containing elevated levels of serum that mimic the in vivo conditions.

In situ hybridization in the histological diagnosis of early and clinically suspect leprosy.

The present study tests the utility of the in situ hybridization procedure for M. leprae rRNA in the histological diagnosis of early leprosy and clinically suspect leprosy, both diagnostically demanding situations. The histological confirmation obtained with routine histopathology (Haematoxylin-Eosin staining for studying morphologic alterations and Fite-Faraco staining for demonstration of acid-fast bacilli) were 32% for early leprosy and 25% for clinically suspect leprosy. With performance of the in situ hybridization on the histologically unconfirmed cases, the positivity rates obtained were 58.8% and 55%, respectively. The results of the study confirm the utility of the procedure in the diagnostically difficult situations of early and suspect leprosy, and it is proposed that the procedure be employed in situations of clinical doubt.