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There is over a hundred years of clinical experience with insulin for the treatment of diabetes. The US Food and Drug Administration (FDA) approved the first insulin biosimilar interchangeable product in 2021 for improving glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Several recombinant insulin products are available in the United States, including the recently approved biosimilar insulins. The approval of the biosimilar insulin products was based on comparative analytical characterizations and comparative pharmacokinetic (PK) and pharmacodynamic (PD) data. The primary objective of this review is to discuss the scientific considerations in the demonstration of biosimilarity of a proposed insulin biosimilar to a reference product and the role of clinical pharmacology studies in the determination of biosimilarity and interchangeability. Euglycemic clamp studies are considered a "gold standard" for insulin PK and PD characterization and have been widely used to determine the time-action profiles of rapid-acting, intermediate-acting, and long-acting insulin products. Clinical pharmacology aspects of study design, including selection of appropriate dose, study population, PK, and PD end points, are presented. Finally, the role of clinical pharmacology studies in the interchangeability assessment of insulin and the regulatory pathways used for insulin and the experience with follow-on insulins and the two recently approved biosimilar insulin products is discussed.

Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens and progestins contained in COCs. It is unavoidable that a woman using COCs may need to take another drug to treat a disease. If the concurrently used drug induces enzymes responsible for the metabolism of progestins and/or estrogens, unintended pregnancy or irregular bleeding may occur. If the concurrent drug inhibits the metabolism of these exogenous hormones, there may be an increased safety risk such as thrombosis. Therefore, for an investigational drug intended to be used in women with reproductive potential, evaluating its effects on the pharmacokinetics of COCs is important to determine if additional labeling is necessary for managing drug-drug interactions (DDIs) between the concomitant product and the COCs. It is challenging to determine when this clinical drug interaction study is needed, whether an observed exposure change of progestin/estrogen is clinically meaningful, and if the results of a clinical drug interaction study with one COC can predict exposure changes of unstudied COCs to inform labeling. In this review, we summarize the current understanding of metabolic pathways of estrogens and progestins contained in commonly used COCs and known interactions of these COCs as victim drugs and we discuss possible mechanisms of interactions for unexpected results. We also discuss recent advances, knowledge gaps, and future perspectives on this important topic. The review will enhance the understanding of DDIs with COCs and improve the safe and effective use of COCs. SIGNIFICANCE STATEMENT: This minireview provides an overview of the metabolic pathways of ethinyl estradiol and progestins contained in commonly used combined oral contraceptives (COCs) and significant drug interactions of these COCs as victims. It also discusses recent advances, knowledge gaps, future perspectives, and potential mechanisms for unexpected results of clinical drug interaction studies of COCs. This minireview will help the reader understand considerations when evaluating the drug interaction potential with COCs for drugs that are expected to be used concurrently.

Determining the amount of drug transferred into human milk is critical for benefit-risk analysis of taking medication while breastfeeding. In this study, we developed an in vitro and in vivo extrapolation (IVIVE) model to predict human milk/plasma (

PURPOSE To estimate hepatobiliary clearances of rosuvastatin via simultaneously fitting to reported human positron emission tomography (PET) data in the liver and gallbladder. METHODS A hepatobiliary model incorporating five intrinsic hepatobiliary clearances (active uptake clearance at the sinusoidal membrane, efflux clearance by passive diffusion through the sinusoidal membrane, influx clearance by passive diffusion through sinusoidal membrane, clearance of biliary excretion at the canalicular membrane, and intercompartment clearance from the intrahepatic bile duct to the gallbladder) and three compartments (liver, intrahepatic bile duct, and gallbladder) was developed to simultaneously fit rosuvastatin liver and gallbladder data from a representative subject reported by Billington et al. (1). Two liver blood supply input functions, arterial input function and dual input function (using peripheral venous as an alternative to portal vein), were assessed. Additionally, the predictive performance between the established model and four reported models trained with only systemic exposure data, was evaluated by comparing simulated liver and gallbladder profiles with observations. RESULTS The established hepatobiliary model well captured the kinetic profiles of rosuvastatin in the liver and gallbladder during the PET scans. Application of dual input function led to a marked underestimation of liver concentrations at the initial stage after i.v. dosing which cannot be offset by altering model parameter values. The simulated hepatobiliary profiles from three of the reported models demonstrated substantial deviation from the observed data. CONCLUSIONS The present study highlights the necessity of using hepatobiliary data to verify and improve the predictive performance of hepatic disposition of rosuvastatin.

Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.

The measurement speed and measurement accuracy of a displacement measuring interferometer are key parameters. To verify these parameters, a fast and high-accuracy motion is required. However, the displacement induced by a mechanical actuator generates disadvantageous features, such as slow motion, hysteresis, distortion, and vibration. This paper proposes a new method for a nonmechanical high-speed motion using an electro-optic modulator (EOM). The method is based on the principle that all displacement measuring interferometers measure the phase change to calculate the displacement. This means that the EOM can be used to accurately generate phase change rather than a mechanical actuator. The proposed method is then validated by placing the EOM into an arm of a frequency modulation interferometer. By using two lock-in amplifiers, the phase change in an EOM and, hence, the corresponding virtual displacement could be measured by the interferometer. The measurement showed that the system could achieve a displacement at 20 kHz, a speed of 6.08 mm/s, and a displacement noise level &lt, 100 pm//√Hz above 2 kHz. The proposed virtual displacement can be applied to determine both the measurement speed and accuracy of displacement measuring interferometers, such as homodyne interferometers, heterodyne interferometers, and frequency modulated interferometers.

For most approved subcutaneously (SC) administered drug products in the US, the recommended injection sites (i.e., abdomen, thigh, and upper arm) are usually based on experience from phase 3 trials. Relative bioavailability data directly comparing the pharmacokinetics (PK) of different SC injection sites are often not available and the underlying mechanisms that may affect SC absorption have not been systematically investigated. In this study, we surveyed clinical PK data (AUC, Cmax, and Tmax) for SC administered drug products including therapeutic proteins and peptides based on literature and FDA database. The PK data after abdominal injection was used as a reference to determine the relative bioavailability of SC injections to the arm and thigh. The survey retrieved 19 immunoglobulin G (IgGs), 18 peptides/small proteins (molecular weight

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients’ access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides ( a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, ( b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and ( c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.

Many orally administered drugs with negative food effects (i.e., lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. The aim of this study is to assess the potential correlation between a negative food effect and biliary excretion. Correlation analysis was conducted using a training dataset containing 27 drugs which met the following criteria: (1) immediate-release formulations, (2) shows a negative food effect, (3) > 10% biliary clearance, and (4) does not undergo extensive metabolism. A correlation between fed-state biliary clearance (CLb,fed) and fasted-state biliary clearance (CLb,fast) (y = 1.81*x, R2 = 0.68) was observed. The 1.8-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effects for 12 test drugs. The mean deviations of predicted fed/fasting AUC ratio and Cmax ratio from clinically observed values were reduced from 32.4 to 17.2% and from 63.3 to 54.3%, respectively. In contrast to the positive food effects on most biopharmaceutics classification system (BCS) class II drugs for which food-stimulated bile flow increases drug solubility and absorption, our results suggest that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in negative food effects.

We evaluated the relative contribution of CYP3A in the overall clearance of commonly used combined oral contraceptives (COCs) based on the results of clinical DDI studies in the literature and new drug applications (NDAs). The results revealed a limited role of CYP3A4 in the metabolism of COC components. Characterization of inhibition or induction spectrum of perpetrators on non‐CYP3A pathways might also be crucial in predicting drug interaction potential of an investigational new drug with COCs.

Hydrotalcites have many important applications in catalysis, wastewater treatment, gene delivery and polymer stabilization, all depending on preparation history and treatment scenarios. In catalysis and polymer stabilization, thermal decomposition is of great importance. Hydrotalcites form easily with atmospheric carbon dioxide and often interfere with the study of other anion containing systems, particularly if formed at room temperature. The dehydroxylation and decomposition of carbonate occurs simultaneously, making it difficult to distinguish the dehydroxylation mechanisms directly. To date, the majority of work on understanding the decomposition mechanism has utilized hydrotalcite precipitated at room temperature. In this study, evolved gas analysis combined with thermal analysis has been used to show that CO2 contamination is problematic in materials being formed at RT that are poorly crystalline. This has led to some dispute as to the nature of the dehydroxylation mechanism. In this paper, data for the thermal decomposition of the chloride form of hydrotalcite are reported. In addition, carbonate-free hydrotalcites have been synthesized with different charge densities and at different growth temperatures. This combination of parameters has allowed a better understanding of the mechanism of dehydroxylation and the role that isomorphous substitution plays in these mechanisms to be delineated. In addition, the effect of anion type on thermal stability is also reported. A stepwise dehydroxylation model is proposed that is mediated by the level of aluminum substitution.

In this study neutron radiography is applied to investigate the performance of a polymer electrolyte membrane (PEM) fuel cell based on the effect of liquid water accumulation in the cell. Dynamic performance tests have been carried out on a PEM fuel cell with a specially designed serpentine flow channel under various operating conditions and simultaneous measurements of accumulated liquid water with neutron imaging. Liquid water tends to accumulate in the gas diffusion layer (GDL) adjacent to the flow channel area while the liquid water formed in the GDL next to the channel land area seems to be effectively removed by the cross leakage flow through the porous GDL between the adjacent flow channels. The amount of liquid water accumulation in the cell is dependant on the cell operating temperature, the pressure drop in the flow channel and the current density under the present test conditions of fixed stoichiometry. It is shown that the cell performance is strongly affected by the presence and accumulation of liquid water, especially at high current densities. This phenomenon results in performance hysteresis for load variations. The rate of liquid water production is also mathematically modeled to analyze the effect of the cell operating temperature and pressure drop on the liquid water formation in a cell. The model result shows good agreement with experimental measurements. The history of liquid water accumulation is also analyzed.

Neutron radiography has been used for in situ and non-destructive visualization and measurement technique for liquid water in a working proton exchange membrane fuel cell (PEMFC). In an attempt to differentiate water distribution in the anode side from that in the cathode side, a specially designed cell was machined and used for the experiment. The major difference between our design and traditional flow field design is the fact the anode channels and cathode channels were shifted by a channel width, so that the anode and cathode channels do not overlap in the majority of the active areas. The neutron radiography experiments were performed at selected relative humidities, and stoichiometry values of cathode inlet. At each operating condition, the water distribution in anode/cathode gas diffusion layers (GDLs) was obtained. Image processing with four different spatial masks was applied to those images to differentiate liquid water in four different types of areas. Results indicate that the reactant gas relative humidity and stoichiometry significantly influence current density distribution and water distribution.

Layered Double Hydroxides (LDH) are being used in energy related research for last several years. Among others, research interests include synthesis of catalysts, electrocatalysts, photocatalysts, electrode materials for batteries and super capacitors, and luminescence materials. They can be also applied for the production of renewable energy sources, such as hydrogen and oxygen. LDH materials have several advantages in general, such as their low cost, versatility of their chemical composition, easily manipulated properties, a wide range of preparation variables, unique anion exchange and intercalation properties, chemical stability, and colloidal and thermal behavior. On the other hand, their use in particular energy research produces some challenging physical and chemical aspects that need to be addressed. These include lack of knowledge on exact structure, postulation of interlayer arrangement, and some selectivity issues in catalysis. In this work, we will revisit these topics with an overview of the historical background and current literature survey.

This paper describes a modelling and dynamic control design process applicable to the development of fuel cell electric vehicles (FCEVs) and hybrid electric vehicles (HEVs). After an introduction to advanced propulsion technologies the development of FCEV at DaimlerChrysler is described, followed by a discussion on hydrogen as a fuel for FCEV and the challenges related to hydrogen storage. It is essential for advanced vehicles to obtain a range comparable to that of mass production vehicles sold today. Thus, there is a strong need to operate such vehicles with high efficiency and maximize the energy stored onboard a vehicle. A stochastic dynamic programming algorithm was developed and applied to the energy management of this FCEV, which allow fuel economy optimisation while keeping a good driveability.

Dermatologic diseases can present in varying forms and severity, ranging from the individual lesion and up to almost total skin involvement. Pharmacokinetic assessment of topical drug products has previously been plagued by bioanalytical assay limitations and the lack of a standardized study design. Since the mid-1990's the US Food and Drug Administration has developed and implemented a pharmacokinetic maximal usage trial (MUsT) design to help address these issues. The MUsT design takes into account the following elements: the enrollment of patients rather than normal volunteers, the frequency of dosing, duration of dosing, use of highest proposed strength, total involved surface area to be treated at one time, amount applied per square centimeter, application method and site preparation, product formulation, and use of a sensitive bioanalytical method that has been properly validated. This paper provides a perspective of pre-MUsT study designs and a discussion of the individual elements that make up a MUsT.

A comprehensive procedure for testing, modeling, and control design of a fuel cell hybrid vehicle (FCHV) is presented in this paper. The subsystems are modeled based on lab testing and in-field vehicle testing results from the DaimlerChrysler Natrium prototype vehicle. An FC-VESIM (fuel cell hybrid vehicle simulation) model is then developed based on the experimental data. The power management control algorithm for the FCHV is subsequently developed based on the stochastic dynamic programming (SDP) technique, which produces an optimal policy for a given probability distribution of the vehicle power demand.

The National Renewable Energy Laboratory (NREL) collaborated with Millennium Cell and DaimlerChrysler to study heat and water management in a sodium borohydride (NaBH 4 ) storage/processor used to supply hydrogen to a fuelcell in an automotive application. Knowledge of heat and water flows in this system is necessary to maximize the storage concentration of NaBH 4 , which increases vehicle range. This work helps evaluate the NaBH 4 system's potential to meet the FreedomCAR program technical target of 6 wt% hydrogen for hydrogen storage technologies. This paper also illustrates the advantages of integrating the NaBH 4 hydrogen processor with the fuel cell.

This paper describes the combustion synthesis (CS) of SrTiO3 using Ti, TiO2, and SrO2. The kinetics of the CS reaction and the effect of the Ti/(Ti+TiO2) ratio on the CS reaction were examined. The thermal behavior of each reactant and the mixture of reactant powders were investigated to study the reaction mechanism. As a result, the oxidation of Ti was found to trigger the CS reaction. The apparent activation energy of the CS reaction was calculated as 287.6 kJ/mol. The obtained results suggest a new route to produce commercially available highly dense ceramics.