The Interpretation of Bioassay and In Vivo Data Using the Proposed ICRP Lung Model and a European Registry of Internal Dose Assessments, Models and Autopsy Data

ABSTRACT Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains of S. aureus (including MRSA), S. pneumoniae (including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log10 kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 μg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T > MIC) correlated best with efficacy for both MRSA and PRSP. The T > MIC values required for the static doses were significantly longer (P < 0.001) for Enterobacteriaceae (36 to 45%) than for S. aureus (14 to 28%) and S. pneumoniae (15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole against S. pneumoniae but only slightly against Klebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new β-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.

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Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients

Frontiers in Pharmacology ◽

10.3389/fphar.2020.585021 ◽

2021 ◽

Vol 11 ◽

Author(s):

Miao Zhang ◽

Xueting Yao ◽

Zhe Hou ◽

Xuan Guo ◽

Siqi Tu ◽

...

Keyword(s):

Pbpk Model ◽

Clinical Findings ◽

Lung Model ◽

Elderly Subjects ◽

Distribution Data ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based ◽

Drug Actions

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

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Automatic application of ICRP biokinetic models in voxel phantoms for in vivo counting and internal dose assessment

Radiation Protection Dosimetry ◽

10.1093/rpd/ncm345 ◽

2007 ◽

Vol 127 (1-4) ◽

pp. 240-244 ◽

Cited By ~ 8

Author(s):

S. Lamart ◽

L. de Carlan ◽

E. Blanchardon ◽

D. Franck

Keyword(s):

Dose Assessment ◽

Internal Dose ◽

Voxel Phantoms

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Correction to: Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption

The AAPS Journal ◽

10.1208/s12248-020-00545-x ◽

2020 ◽

Vol 23 (1) ◽

Author(s):

Johanna Eriksson ◽

Erik Sjögren ◽

Hans Lennernäs ◽

Helena Thörn

Keyword(s):

Drug Absorption ◽

Lung Model ◽

Rat Lung

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Pulmonary Metabolism of Substrates for Key Drug-Metabolizing Enzymes by Human Alveolar Type II Cells, Human and Rat Lung Microsomes, and the Isolated Perfused Rat Lung Model

Pharmaceutics ◽

10.3390/pharmaceutics12020117 ◽

2020 ◽

Vol 12 (2) ◽

pp. 117

Author(s):

Katarina Rubin ◽

Pär Ewing ◽

Erica Bäckström ◽

Anna Abrahamsson ◽

Britta Bonn ◽

...

Keyword(s):

Human Lung ◽

Limit Of Detection ◽

Lung Model ◽

Alveolar Type ◽

Metabolic Clearance ◽

Drug Metabolizing Enzymes ◽

Type Ii ◽

Rat Lung ◽

Metabolizing Enzymes

Significant pulmonary metabolism of inhaled drugs could have drug safety implications or influence pharmacological effectiveness. To study this in vitro, lung microsomes or S9 are often employed. Here, we have determined if rat and human lung microsomes are fit for purpose or whether it is better to use specific cells where drug-metabolizing enzymes are concentrated, such as alveolar type II (ATII) cells. Activities for major hepatic and pulmonary human drug-metabolizing enzymes are assessed and the data contextualized towards an in vivo setting using an ex vivo isolated perfused rat lung model. Very low rates of metabolism are observed in incubations with human ATII cells when compared to isolated hepatocytes and fewer of the substrates are found to be metabolized when compared to human lung microsomal incubations. Reactions selective for flavin-containing monooxygenases (FMOs), CYP1B1, CYP2C9, CYP2J2, and CYP3A4 all show significant rates in human lung microsomal incubations, but all activities are higher when rat lung microsomes are used. The work also demonstrates that a lung microsomal intrinsic clearance value towards the lower limit of detection for this parameter (3 µL/min/mg protein) results in a very low level of pulmonary metabolic clearance during the absorption period, for a drug dosed into the lung in vivo.

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Replicating Adenoviruses That Target Tumors with Constitutive Activation of the wnt Signaling Pathway

Journal of Virology ◽

10.1128/jvi.75.6.2857-2865.2001 ◽

2001 ◽

Vol 75 (6) ◽

pp. 2857-2865 ◽

Cited By ~ 51

Author(s):

Michele Brunori ◽

Maddalena Malerba ◽

Haruhiko Kashiwazaki ◽

Richard Iggo

Keyword(s):

Wnt Signaling ◽

Cancer Cells ◽

Wnt Pathway ◽

Wnt Signaling Pathway ◽

Lung Model ◽

Colorectal Tumors ◽

Colon Tumors ◽

Treat All

ABSTRACT Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which rationally target known causal oncogenic defects. Selectively replicating viruses have a major advantage over nonreplicating viruses to target these defects because the therapeutic effect of the injected virus is augmented by virus produced within the tumor. To permit rational targeting of colon tumors, we have developed replicating adenoviruses that express the viral E1B and E2 genes from promoters controlled by the Tcf4 transcription factor. Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and β-catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue. The Tcf-E2 and Tcf-E1B promoters are active in many, but not all, cell lines with activation of the wnt pathway. Viruses with Tcf regulation of E2 expression replicate normally in SW480 colon cancer cells but show a 50- to 100-fold decrease in replication in H1299 lung cancer cells and WI38 normal fibroblasts. Activation of wnt signaling by transduction of a stable β-catenin mutant into normal fibroblasts renders the cells permissive for virus replication. Insertion of Tcf4 sites in the E1B promoter has only small effects on replication in vitro but significantly reduces the inflammatory response in a rodent lung model in vivo. Replicating adenoviruses with Tcf regulation of both E1B and E2 transcription are potentially useful for the treatment of liver metastases from colorectal tumors, but additional changes will be required to produce a virus that can be used to treat all colon tumors.

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EURADOS coordinated action on research, quality assurance and training of internal dose assessments

Radiation Protection Dosimetry ◽

10.1093/rpd/ncq435 ◽

2010 ◽

Vol 144 (1-4) ◽

pp. 349-352 ◽

Cited By ~ 12

Author(s):

M. A. Lopez ◽

I. Balashazy ◽

P. Berard ◽

E. Blanchardon ◽

B. Breustedt ◽

...

Keyword(s):

Quality Assurance ◽

Research Quality ◽

Internal Dose ◽

Coordinated Action ◽

And Training ◽

Dose Assessments

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In vitro and in vivo functional residual capacity comparisons between multiple-breath nitrogen washout devices

ERJ Open Research ◽

10.1183/23120541.00011-2017 ◽

2017 ◽

Vol 3 (4) ◽

pp. 00011-2017 ◽

Cited By ~ 7

Author(s):

Katrina O. Tonga ◽

Paul D. Robinson ◽

Claude S. Farah ◽

Greg G. King ◽

Cindy Thamrin

Keyword(s):

Functional Residual Capacity ◽

Measurement Accuracy ◽

Lung Model ◽

Nitrogen Washout ◽

Device Validation ◽

Residual Capacity

Functional residual capacity (FRC) accuracy is essential for deriving multiple-breath nitrogen washout (MBNW) indices, and is the basis for device validation. Few studies have compared existing MBNW devices. We evaluated in vitro and in vivo FRC using two commercial MBNW devices, the Exhalyzer D (EM) and the EasyOne Pro LAB (ndd), and an in-house device (Woolcock in-house device, WIMR).FRC measurements were performed using a novel syringe-based lung model and in adults (20 healthy and nine with asthma), followed by plethysmography (FRCpleth). The data were analysed using device-specific software. Following the results seen with ndd, we also compared its standard clinical software (ndd v.2.00) with a recent upgrade (ndd v.2.01).WIMR and EM fulfilled formal in vitro FRC validation recommendations (>95% of FRC within 5% of known volume). Ndd v.2.00 underestimated in vitro FRC by >20%. Reanalysis using ndd v.2.01 reduced this to 11%, with 36% of measurements ≤5%. In vivo differences from FRCpleth (mean±sd) were 4.4±13.1%, 3.3±11.8%, −20.6±11% (p<0.0001) and −10.5±10.9% (p=0.005) using WIMR, EM, ndd v.2.00 and ndd v.2.01, respectively.Direct device comparison highlighted important differences in measurement accuracy. FRC discrepancies between devices were larger in vivo, compared to in vitro results; however, the pattern of difference was similar. These results represent progress in ongoing standardisation efforts.

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Bronchoscopically delivered microwave ablation in an in vivo porcine lung model

ERJ Open Research ◽

10.1183/23120541.00146-2020 ◽

2020 ◽

Vol 6 (4) ◽

pp. 00146-2020

Author(s):

Jan Sebek ◽

Steve Kramer ◽

Rob Rocha ◽

Kun-Chang Yu ◽

Radoslav Bortel ◽

...

Keyword(s):

Microwave Ablation ◽

Early Stage ◽

Lung Parenchyma ◽

Lung Model ◽

Guidance System ◽

Lung Tumour ◽

Virtual Bronchoscopy ◽

Invasive Treatment ◽

Technical Feasibility

BackgroundPercutaneous microwave ablation is clinically used for inoperable lung tumour treatment. Delivery of microwave ablation applicators to tumour sites within lung parenchyma under virtual bronchoscopy guidance may enable ablation with reduced risk of pneumothorax, providing a minimally invasive treatment of early-stage tumours, which are increasingly detected with computed tomography (CT) screening. The objective of this study was to integrate a custom microwave ablation platform, incorporating a flexible applicator, with a clinically established virtual bronchoscopy guidance system, and to assess technical feasibility for safely creating localised thermal ablations in porcine lungs in vivo.MethodsPre-ablation CTs of normal pigs were acquired to create a virtual model of the lungs, including airways and significant blood vessels. Virtual bronchoscopy-guided microwave ablation procedures were performed with 24–32 W power (at the applicator distal tip) delivered for 5–10 mins. A total of eight ablations were performed in three pigs. Post-treatment CT images were acquired to assess the extent of damage and ablation zones were further evaluated with viability stains and histopathologic analysis.ResultsThe flexible microwave applicators were delivered to ablation sites within lung parenchyma 5–24 mm from the airway wall via a tunnel created under virtual bronchoscopy guidance. No pneumothorax or significant airway bleeding was observed. The ablation short axis observed on gross pathology ranged 16.5–23.5 mm and 14–26 mm on CT imaging.ConclusionWe have demonstrated the technical feasibility for safely delivering microwave ablation in the lung parenchyma under virtual bronchoscopic guidance in an in vivo porcine lung model.

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