Molecular structure, NBO analysis of the hydrogen-bonded interactions, spectroscopic (FT-IR, FT-Raman), drug likeness and molecular docking of the novel anti COVID-2 molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide (Dimer) - quantum chemical approach.

Prospective antiviral molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been probed using Fourier transform infrared (FTIR), FT-Raman and quantum chemical computations. The geometry equilibrium and natural bond orbital analysis have been carried out with density functional theory employing Becke, 3-parameter, Lee-Yang-Parr method with the 6-311G++(d,p) basis set. The vibrational assignments pertaining to different modes of vibrations have been augmented by normal coordinate analysis, force constant and potential energy distributions. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. The inhibiting potency of 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been investigated by docking simulation against SARS-CoV-2 protein. The optimized geometry shows a planar structure between the chromone and the side chain. Differences in the geometries due to the substitution of the electronegative atom and intermolecular contacts due to the chromone and hydrazinecarbothioamide were analyzed. NBO analysis confirms the presence of two strong stable hydrogen bonded NH⋯O intermolecular interactions and two weak hydrogen bonded CH⋯O interactions. The red shift in NH stretching frequency exposed from IR substantiates the formation of NH⋯O intermolecular hydrogen bond and the blue shift in CH stretching frequency substantiates the formation of CH⋯O intermolecular hydrogen bond. Drug likeness, absorption, distribution, metabolism, excretion and toxicity property gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of the nonbonding interaction with Histidine 41 and Cysteine 145, present a clear view that 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide can irreversibly interact with SARS-CoV-2 protease.

Simultaneous Quantitative Analysis of Six Proton-Pump Inhibitors with a Single Marker and Evaluation of Stability of Investigated Drugs in Polypropylene Syringes for Continuous Infusion Use.

OBJECTIVE: We developed and validated a simple, convenient and reproducible method for simultaneous estimation of six proton-pump inhibitors (PPIs), omeprazole (OPZ), esomeprazole (EOPZ), lansoprazole (LPZ), pantoprazole (PPZ), rabeprazole (RPZ) and ilaprazole (IPZ) in pharmaceutical dosage forms by a single marker. Meanwhile, the stability of the cited PPIs in 0.9% sodium chloride injection stored in polypropylene syringes up to 48 hours for continuous infusion use was investigated. MATERIALS AND METHODS: The chromatographic separation was achieved on an InterSustain® C18 column (150 × 4.6 mm, 5 µm). The isocratic mobile phase made up of 0.05 M potassium dihydrogen phosphate buffer (pH 4.0): acetonitrile (65:35, v/v) was pumped through the column at a temperature maintained at 30°C and a flow rate of 1.0 mL/min. The relative retention time, UV spectral similarity and relative correction factors between OPZ and the other five PPIs were calculated and investigated using the quantitative analysis of multi-components with a single marker (QAMS) method. The stability study examined physical parameters, pH values and drug concentrations of the PPIs mixtures. RESULTS: Under these conditions, all cited PPIs were separated simultaneously at a retention time of 6.0, 7.3, 7.3, 9.9, 12.5 and 13.9 min for RPZ, OPZ, EOPZ, IPZ, PPZ and LPZ, respectively, with a total run time less than 20.0 min. Comparative analysis results indicated that there were no significant differences observed between the QAMS method and the external standard method. The percentage of initial concentration of each PPI gradually decreased during the storage time. CONCLUSION: The proposed method, which is selective, economical and accurate, was applied successfully for determination of the cited PPIs in their respective pharmaceutical dosage forms. Admixtures of OPZ, EOPZ, PPZ, IPZ in 0.9% sodium chloride injection were stable for 24 hours and LPZ, RPZ in 0.9% sodium chloride injection were stable for 8 hours in polypropylene syringes.

The Applications of Sensors and Biosensors in Investigating Drugs, Foods, and Nutraceuticals.

The present Special Issue is focused on developing and applying several sensors, biosensor devices, and actuators for the analysis of drugs, foods, and nutraceuticals. Some applications concern classical topics, such as clostridium determination in dairy products, flavouring material in foods like ethylvanillin, or the antioxidant properties of fruit juices, while other applications are more innovative, such as food safety analysis, artificial human senses (electronic nose, or tongue) development, or ethanol determination in pharmaceutical drugs, or forensic purposes using catalytic fuel cell; and lastly, new studies devoted to intelligent food packaging. Therefore, this Special Issue should interest both specialists in the sector and readers who are simply curious, or are simply interested in innovations in the field of food and drug analysis.

Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma.

The emergence of Mycobacterium tuberculosis strains resistant to current first-line antibiotic regimens constitutes a major global health threat. New treatments against multidrug-resistant tuberculosis (MDR-TB) are thus eagerly needed in particular in countries with a high MDR-TB prevalence. In this context, macozinone (PBTZ169), a promising drug candidate with an unique mode of action and highly potent in vitro tuberculocidal properties against MDR Mycobacterium strains, has now reached the clinical phase and has been notably tested in healthy male volunteers in Switzerland. To that endeavor, a multiplex UHPLC-MS/MS method has been developed for the sensitive and accurate human plasma levels determination of PBTZ169 along with five metabolites retaining in vitro anti-TB activity. Plasma protein precipitation with methanol was carried out as a simplified sample clean-up procedure followed by direct injection of the undiluted supernatant for the bioanalysis of the six analytes within 5 min, using 1.8 µm reversed-phase chromatography coupled to triple quadrupole mass spectrometry employing electrospray ionization in the positive mode. Stable isotopically-labelled PBTZ169 was used as internal standard (ISTD), while metabolites could be reliably quantified using two unlabeled chemical analogues selected as ISTD from a large in-house analogous compounds library. The overall methodology was fully validated according to current recommendations (FDA, EMEA) for bioanalytical methods, which include selectivity, carryover, qualitative and quantitative matrix effect, extraction recovery, process efficiency, trueness, precision, accuracy profiles, method and instrument detection limits, integrity to dilution, anticoagulant comparison and short- and long-term stabilities. Stability studies on the reduced metabolite H2-PBTZ169 have shown no significant impact on the actual PBTZ169 concentrations determined with the proposed assay. This simplified, rapid, sensitive and robust methodology has been applied to the bioanalysis of human plasma samples collected within the frame of a phase I clinical study in healthy volunteers receiving PBTZ169.

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease.

Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein.

Incurred sample reanalysis in drug discovery bioanalysis.

Bioanalysis plays a key role during the drug discovery process to generate the pharmacokinetic data to facilitate unbiased evaluation of leads, optimized leads and drug candidates. Such pharmacokinetic data are used to enable key decisions in the drug discovery process. The aim of the work is to put forward a new strategy of performing the incurred sample reanalysis for select small molecule novel chemical entities at different stages of drug discovery prior to candidate selection. Three discovery programs representing hits, leads and optimized lead candidates were selected for the incurred sample reanalysis (ISR) analysis. From each discovery program, two novel chemical entities were selected for the ISR analysis. The time points considered for ISR generally varied among the programs; however, samples coinciding with drug absorption, distribution and elimination were considered in the ISR assessment. With the exception of a single ISR value that gave a high deviation (about 63%), the observed ISR values supported the discovery bioanalytical assays. While the individual bioanalytical laboratory can draw an algorithm for selecting novel chemical entities and fixing the acceptance criteria for the ISR data, it is proposed that the percentage difference between ISR vs. original concentration for 67% of the repeat samples is contained within ±30% for discovery bioanalysis.

Emerging technologies for biotherapeutic bioanalysis from a high-throughput and multiplexing perspective: insights from an AAPS emerging technology action program committee.

This manuscript aims to provide insights and updates on emerging technologies from a throughput and multiplexing perspective and to update readers on changes in previously reported technologies. The technologies discussed range from nascent (ultrasensitive Cira, Intellicyt®, Dynaxi and Captsure™) to the more established (Ella and SQIDlite™). For the nascent technologies, there was an emphasis on user interviews and reviews, where available, to help provide an unbiased view to our readers. For the Ella, a review of published user data as well as author and other user experiences are summarized. Due to their emergent nature, all the technologies described are applicable in the early drug development stage, may require an upfront investment of capital and may not perform as expected.

Nanocristais de hidroximetilnitrofural: preparação, caracterização fí­sico-quí­mica, avaliação da atividade in vitro antileishmania / Hydroxymethylnitrofurazone nanocrystals: optimization, characterization, leishmanicidal activity evaluation

De acordo com a Organização Mundial de Saúde, existem atualmente 17 doenças tropicais negligenciadas prevalentes em 149 países, afetando aproximadamente um bilhão de pessoas, a nível global. A leishmaniose, problema de saúde prevalente nos países em desenvolvimento, é endêmica em aproximadamente 98 países e territórios, com 350 milhões de pessoas em risco e 12 milhões de casos de infecção no mundo. A transmissão da doença ocorre pela picada de flebotomíneos fêmeas infectadas. Essa doença apresenta três formas principais: leishmaniose cutânea (LC), leishmaniose mucocutânea (LMC) e leishmaniose visceral (LV). Enquanto a leishmaniose cutânea é a forma mais comum da doença, a leishmaniose visceral é a mais grave e pode ser fatal se não for tratada. Em 2016, o Brasil reportou 3.626 e 12.690 casos de LC e LV, respectivamente. O candidato a fármaco hidroximetilnitrofural (NFOH) mostrou atividade contra o parasita da doença de chagas e da leishmaniose. Embora o NFOH seja promissor para o tratamento da leishmaniose, esse possui baixa solubilidade em água. A nanotecnologia tem sido empregada como plataforma para o desenvolvimento de formas farmacêuticas inovadoras com maior eficácia e segurança. A redução do tamanho de partículas em escala nanométrica permite aumentar a biodisponibilidade oral de fármacos pouco solúveis em água. Os nanocristais apresentam vantagens, tais como, o aumento da solubilidade de saturação e da velocidade de dissolução, decorrentes do aumento da área superficial da partícula. Além disso, esses apresentam maior adesividade às membranas biológicas, membrana celular e superfície do trato gastrointestinal. No presente trabalho utilizou-se a moagem por via úmida em escala reduzida para a obtenção dos nanocristais de NFOH. Diferentes tensoativos foram avaliados empregando o método selecionado, os tensoativos poloxamer 188 e poloxamer 407 foram os que favoreceram a redução do tamanho das partículas. Tal característica foi observada na caracterização físico-química das nanosuspensões de NFOH. A utilização desse método permitiu a obtenção de nanocristais de NFOH, com diâmetro hidrodinâmico médio (DHM) de 184,8 ± 0,5 a 325,9 ± 2,2 nm, índice de polidispersão (IP) de 0,21 ± 0,01 a 0,57 ± 0,01 e DHM de 191,3 ± 2,1 a 326,8 ± 4,6 nm e IP de 0,21 ± 0,01 a 0,50 ± 0,01, respectivamente para o poloxamer 188 e 407. O uso de ambos os tensoativos resultaram em distribuição monomodal de tamanho das partículas. As formulações foram obtidas por meio de planejamento fatorial completo e experimentos por superfície de resposta tendo como variáreis independentes as concentrações de NFOH, dos tensoativos e o tempo de moagem. A resposta, DHM, foi determinada utilizando espalhamento de luz dinâmica (DLS). Adicionalmente, as avaliações empregando calorimetria exploratória diferencial (DSC) e difração de raio X (DRX) revelaram que não houve interação entre o fármaco e os excipientes, assim como, não foi observada alteração na estrutura cristalina do NFOH. A microscopia eletrônica de varredura demonstrou a morfologia característica do estado cristalino. Além disso, a preparação liofilizada apresentou instabilidade após armazenamento por três meses a temperatura de 25 e 4 °C

According to the World Health Organization, there are currently 17 neglected tropical diseases prevalent in 149 countries, affecting approximately one billion people globally. Leishmaniasis, a health problem prevalent in developing countries, is endemic in approximately 98 countries and territories, with 350 million people at risk and 12 million cases of infection worldwide. The transmission of the disease occurs by the bite of infected female sandflies. This disease has three main forms: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL) and visceral leishmaniasis (VL). While cutaneous leishmaniasis is the most usual form of the disease, visceral leishmaniasis is the most serious and can be fatal if left untreated. In 2016, Brazil reported 3.626 and 12.690 cases of LC and LV, respectively. The drug candidate for hydroxymethylnitrofurazone (NFOH) showed activity against the parasite of chagas disease and leishmaniasis. Although NFOH is promising for the treatment of leishmaniasis, it has low solubility in water. Nanotechnology has been used as a platform for the development of innovative pharmaceutical forms with greater effectiveness and safety. Particle size reduction on the nanoscale enables the oral bioavailability of poorly water-soluble drugs to be increased. Nanotechnology has been used as a platform for the development of innovative pharmaceutical forms, improving effectiveness and safety. Particle size reduction on the nanoscale enables the oral bioavailability of poorly water-soluble drugs to be increased. Nanocrystals have advantages such as increased saturation solubility and dissolution rate due to the increase in the surface area of the particle. In addition, this present greater adhesiveness to the biological membranes, cell membrane and surface of the gastrointestinal tract. In the present work, wet scale milling was used to obtain NFOH nanocrystals. Different surfactants were evaluated using the selected method, poloxamer 188 and poloxamer 407 surfactants favored the reduction of particle size. This characteristic was observed in the physical-chemical characterization of NFOH nanosuspensions. The use of NFOH nanocrystals with a mean hydrodynamic diameter (DHM) of 184.8 ± 0.5 to 325.9 ± 2.2 nm, polydispersity index (IP) of 0.21 ± 0, 01 to 0.57 ± 0.01 for poloxamer 188 and DHM of 191.3 ± 2.1 at 326.8 ± 4.6 nm and IP of 0.21 ± 0.01 at 0.50 ± 0.01 for poloxamer 407, both with monomodal size distribution. The formulations were obtained by means of complete factorial planning and surface response experiments having as independent variables the concentrations of NFOH, surfactants and milling time. The response, DHM, was determined using dynamic light scattering (DLS). In addition, evaluations using differential scanning calorimetry (DSC) and X-ray diffraction (DRX) revealed that there was no change in the crystal structure of NFOH and interaction between the drug and the excipients. Scanning electron microscopy demonstrated the characteristic morphology of the crystalline state. In addition, the lyophilized preparation was instable after storage for three months at 25 and 4 ° C

Determination of AZD6118 in dog plasma samples utilizing microextraction by packed sorbent and liquid chromatography-electrospray ionization tandem mass spectrometry.

In this work, for the first time, a method has been developed for the determination of AZD6118, a candidate drug, in dog plasma samples. The method is based on microextraction by packed sorbent (MEPS) of the drug prior to liquid chromatography-electrospray ionization tandem mass spectrometry assay. Various important factors affecting MEPS performance were optimized, and under the optimized condition, a linear calibration curve in the concentration range of 20-25,000nmolL-1 with a coefficient of determination over 0.99 was obtained. The back-calculated values of the calibration points showed good agreement with the theoretical concentrations (coefficients of variation percent between 0.3-3.8). The lower limit of quantification and limit of detection were 20.0 and 2.9nmolL-1, respectively. The repeatability and accuracy of the method was evaluated by determination of quality control samples at three concentration levels (low, medium and high) using the developed method, and the results (coefficients of variation values were between 1.9% and 3.2%, relative recoveries ranged between 93.5-102.1%) confirm that a powerful method has been developed for the extraction and determination of the investigated drug in dog plasma.

Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers.

AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first-in-man, single and repeat dose-escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once-daily treatment. Plasma exposure suggested dose-proportional pharmacokinetics and dose-related effects on 24-hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA-S and 4ß-OH-cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus-pituitary-adrenal (HPA) effects appeared to be marginally greater in the Japanese- versus the Caucasian-dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 µg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit-risk ratio may be improved relative to conventional inhaled steroids.

A clinical pharmacokinetic microdosing study of docetaxel with Japanese patients with cancer.

PURPOSE: Whether microdosing studies can be used to evaluate the human pharmacokinetics of new anticancer drugs remains unclear. The disposition of docetaxel in cancer patients is linear in terms of dose proportionality. We examined whether the pharmacokinetics of docetaxel in a clinically relevant therapeutic dose could be predicted from the pharmacokinetics of a microdose of docetaxel in Japanese patients with cancer. METHODS: A microdose of docetaxel (100 µg/patient) was given by 5-min intravenous infusion on day 1, followed by a therapeutic dose of docetaxel (60-75 mg m(-2)), given by 1-h intravenous infusion on day 8. Plasma docetaxel was analyzed by liquid chromatography-tandem mass spectrometry. A two-compartment pharmacokinetic model was used to calculate the area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf). RESULTS: Nine patients received both a microdose and therapeutic dose of docetaxel. The AUC0-inf after microdosing was 3640 ± 1150 ng h L(-1), while that after therapeutic dosing adjusted to 100 mg/patient was 2230 ± 757 µg h L(-1). The ratio of docetaxel clearance in therapeutic dose to that in microdose was 1.8 (P = 0.0041). Plasma α1-acid glycoprotein concentrations negatively correlated with docetaxel clearance at therapeutic dose, whereas the trend was weak at microdose. CONCLUSION: Docetaxel clearance showed marginal nonlinearity between microdose and therapeutic dose, presumably because of saturation of plasma protein binding; however, the magnitude was within twofold, allowing practically acceptable extrapolation.

A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834.

GDC-0834, a Bruton's tyrosine kinase inhibitor investigated as a potential treatment of rheumatoid arthritis, was previously reported to be extensively metabolized by amide hydrolysis such that no measurable levels of this compound were detected in human circulation after oral administration. In vitro studies in human liver cytosol determined that GDC-0834 (R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b] thiophene-2-carboxamide) was rapidly hydrolyzed with a CLint of 0.511 ml/min per milligram of protein. Aldehyde oxidase (AO) and carboxylesterase (CES) were putatively identified as the enzymes responsible after cytosolic fractionation and mass spectrometry-proteomics analysis of the enzymatically active fractions. Results were confirmed by a series of kinetic experiments with inhibitors of AO, CES, and xanthine oxidase (XO), which implicated AO and CES, but not XO, as mediating GDC-0834 amide hydrolysis. Further supporting the interaction between GDC-0834 and AO, GDC-0834 was shown to be a potent reversible inhibitor of six known AO substrates with IC50 values ranging from 0.86 to 1.87 µM. Additionally, in silico modeling studies suggest that GDC-0834 is capable of binding in the active site of AO with the amide bond of GDC-0834 near the molybdenum cofactor (MoCo), orientated in such a way to enable potential nucleophilic attack on the carbonyl of the amide bond by the hydroxyl of MoCo. Together, the in vitro and in silico results suggest the involvement of AO in the amide hydrolysis of GDC-0834.

Mechanistic investigation of the preclinical pharmacokinetics and interspecies scaling of PF-05231023, a fibroblast growth factor 21-antibody protein conjugate.

PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG1 κ scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.

Evidencias actuales de los nuevos anticoagulantes orales en el tratamiento de la fibrilación auricular no valvular: comparación de subestudios / Current evidence for new oral anticoagulants in the treatment of nonvalvular atrial fibrillation: comparison of substudies

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Translating dosages from animal models to human clinical trials--revisiting body surface area scaling.

Body surface area (BSA) scaling has been used for prescribing individualized dosages of various drugs and has also been recommended by the U.S. Food and Drug Administration as one method for using data from animal model species to establish safe starting dosages for first-in-human clinical trials. Although BSA conversion equations have been used in certain clinical applications for decades, recent recommendations to use BSA to derive interspecies equivalents for therapeutic dosages of drug and natural products are inappropriate. A thorough review of the literature reveals that BSA conversions are based on antiquated science and have little justification in current translational medicine compared to more advanced allometric and physiologically based pharmacokinetic modeling. Misunderstood and misinterpreted use of BSA conversions may have disastrous consequences, including underdosing leading to abandonment of potentially efficacious investigational drugs, and unexpected deadly adverse events. We aim to demonstrate that recent recommendations for BSA are not appropriate for animal-to-human dosage conversions and use pharmacokinetic data from resveratrol studies to demonstrate how confusion between the "human equivalent dose" and "pharmacologically active dose" can lead to inappropriate dose recommendations. To optimize drug development, future recommendations for interspecies scaling must be scientifically justified using physiologic, pharmacokinetic, and toxicology data rather than simple BSA conversion.

Development of a convenient ex vivo model for the study of the transcorneal permeation of drugs: histological and permeability evaluation.

In this paper, an ex vivo model for the study of the transcorneal permeation of drugs, based on porcine tissues, was evaluated. The setup is characterized by ease of realization, absence of O2 and CO2 bubbling and low cost; additionally, the large availability of porcine tissue permits a high throughput. Histological images showed the comparability between porcine and human corneas and confirmed the effectiveness of the isolation procedure. A new de-epithelization procedure based on a thermal approach was also set up to simulate cornea permeability in pathological conditions. The procedure did not affect the integrity of the underlying layers and allowed the characterization of the barrier properties of epithelium and stroma. Six compounds with different physicochemical properties were tested: fluorescein, atenolol, propranolol, diclofenac, ganciclovir and lidocaine. The model highlighted the barrier function played by epithelium toward the diffusion of hydrophilic compounds and the permselectivity with regard to more lipophilic molecules. In particular, positively charged compounds showed a significantly higher transcorneal permeability than negatively charged compounds. The comparability of results with literature data supports the goodness and the robustness of the model, especially taking into account the behavior of fluorescein, which is generally considered a marker of tissue integrity.

Population pharmacokinetics of HM781-36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in patients with advanced solid malignancies.

PURPOSE: To develop a population pharmacokinetic (PK) model for HM781-36 (poziotinib) and its metabolites in cancer patients. METHODS: Blood samples were collected from three phase I studies in which fifty-two patients received oral HM781-36B tablets (0.5-32 mg) once daily for 2 weeks, and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) in fasting (12 patients) or fed (eight patients) state once daily for 4 weeks. Nonlinear mixed effect modeling was employed to develop the population pharmacokinetic model. RESULTS: HM781-36 PK was ascribed to a two-compartment model and HM781-36-M1/-M2 PK to one-compartment model. HM781-36 oral absorption was characterized by first-order input (absorption rate constant: 1.45 ± 0.23 h⁻¹). The central volume of distribution (185 ± 12.7 L) was influenced significantly by body weight. The absorption rate constant was influenced by food. The typical HM781-36 apparent clearance was 34.5 L/h (29.4 %CV), with an apparent peripheral volume of distribution of 164 L (53.5 %CV). Other covariates did not significantly further explain the PKs of HM781-36. CONCLUSIONS: The proposed model suggests that HM781-36 PKs are consistent across most solid tumor types, and that the absorption process of HM781-36 is affected by the fed state before dosing. HM781-36 PKs are not complicated by patient factors, other than body weight.

Biological evaluation of a novel sorafenib analogue, t-CUPM.

Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.

Microenvironmental pH-modified solid dispersions to enhance the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug: preparation, characterization and evaluation in vivo.

The aim of the present work was to design a pH-modified solid dispersion (pH(M)-SD) that can improve the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug. To select the appropriate acidifiers, a solubility test was carried out first. Solid dispersions (SDs) containing GT0918 and polyvinylpyrrolidone (PVP) were prepared using a solvent evaporation method and were characterized using dissolution studies in different media. The solid states of the SDs were investigated using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). The in vivo pharmacokinetics of the pH(M)-SDs tablets were also studied in beagle dogs compared to the conventional tablets. The optimized pH(M)-SD (GT0918/PVP/citric acid, 1:2:2 weight ratio) exhibited a significant improvement in the dissolution behavior compared to both the physical mixture and the binary SDs. Solid-state characterization revealed that the amorphous formation of GT0918 in the SDs and the strong H-bonding were only found in the pH(M)-SDs containing citric acid. Furthermore, the GT0918-loaded pH(M)-SD tablets showed a higher AUC and a lower tmax compared to the conventional tablets. Accordingly, the pH(M)-SD might be an efficient route for enhancing the dissolution and bioavailability of poorly water-soluble GT0918.

Comparing translational population-PBPK modelling of brain microdialysis with bottom-up prediction of brain-to-plasma distribution in rat and human.

The prediction of brain extracellular fluid (ECF) concentrations in human is a potentially valuable asset during drug development as it can provide the pharmacokinetic input for pharmacokinetic-pharmacodynamic models. This study aimed to compare two translational modelling approaches that can be applied at the preclinical stage of development in order to simulate human brain ECF concentrations. A population-PBPK model of the central nervous system was developed based on brain microdialysis data, and the model parameters were translated to their corresponding human values to simulate ECF and brain tissue concentration profiles. In parallel, the PBPK modelling software Simcyp was used to simulate human brain tissue concentrations, via the bottom-up prediction of brain tissue distribution using two different sets of mechanistic tissue composition-based equations. The population-PBPK and bottom-up approaches gave similar predictions of total brain concentrations in both rat and human, while only the population-PBPK model was capable of accurately simulating the rat ECF concentrations. The choice of PBPK model must therefore depend on the purpose of the modelling exercise, the in vitro and in vivo data available and knowledge of the mechanisms governing the membrane permeability and distribution of the drug.