Oncolytic viral kinetics mechanistic modeling of Talimogene Laherparepvec (T-VEC) a first-in-class oncolytic viral therapy in patients with advanced melanoma.

Talimogene Laherparepvec (T-VEC) is a first-in-class oncolytic virotherapy approved for the treatment of unresectable melanoma recurrent after initial surgery. Biodistribution data from a phase II study was used to develop a viral kinetic mechanistic model describing the interaction between cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), the immune system, and T-VEC treatment. Our analysis found that (1) the viral infection rate has a great influence on T-VEC treatment efficacy; (2) an increase in T-VEC dose of 102 plaque-forming units/ml 21 days and beyond after the initial dose of T-VEC resulted in an ~12% increase in response; and (3) at the systemic level, the ratio of resting innate immune cells to the death rate of innate immune impact T-VEC treatment efficacy. This analysis clarifies under which condition the immune system either assists in eliminating tumor cells or inhibits T-VEC treatment efficacy, which is critical to both efficiently design future oncolytic agents and understand cancer development.

Recent advances and clinical pharmacology aspects of Chimeric Antigen Receptor (CAR) T-cellular therapy development.

Advances in immuno-oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno-therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non-solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno-therapies, especially CAR-T cells. Here, we summarize the current knowledge of TCR and CAR-T cell immunotherapy with particular focus on the structure of CAR-T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR-T cell therapies are described.

[Current developments in healthcare information technology : Impact on structured reporting]. / Gegenwärtige Entwicklungen in der Healthcare-Informationstechnologie : Auswirkungen auf die strukturierte Befundung.

Structured reporting has become established in many radiological applications over the last 20 years. However, its significance is often still seen as being limited to a narrow section of clinical workflows-image reporting and the creation of radiological reports. By placing every clinical and radiological finding in a semantic context from which its clinical meaning can be reproduced at any time, even by digital assistance systems, structured handling of medical data is essential for the interoperability of clinical systems along the entire diagnostic and therapeutic pathway.

Panitumumab: A Review of Clinical Pharmacokinetic and Pharmacology Properties After Over a Decade of Experience in Patients with Solid Tumors.

Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors expressing EGFR. Panitumumab received approval in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer. Over the last 10 years, the pharmacokinetic and pharmacodynamic profile of panitumumab has been studied to further evaluate its safety, efficacy, and optimal dosing regimen. In this review, we summarize the key clinical pharmacokinetic and pharmacology data for panitumumab, and considerations for its use in special populations. Panitumumab has a nonlinear pharmacokinetic profile and its approved dosing regimen (6 mg/kg every 2 weeks) is based on body weight; dose adjustments are not needed based on sex, age, or renal or hepatic impairment. Drug interactions do not occur when panitumumab is combined with chemotherapy drugs including irinotecan, paclitaxel, and carboplatin. The level of tumor EGFR expression was found to have no effect on panitumumab pharmacokinetics or efficacy. The incidence of anti-panitumumab antibodies is low; when anti-panitumumab antibodies are produced, they do not affect the efficacy, safety, or pharmacokinetics of panitumumab. In summary, the pharmacokinetic and pharmacodynamic profile of panitumumab is well suited for standard dosing, and the approved body weight-based dosing regimen maintains efficacy and safety in the treatment of wild-type RAS metastatic colorectal cancer across a broad range of patients.

Quantitative determination of armodafinil in human plasma by liquid chromatography-electrospray mass spectrometry: Application to a clinical study.

Armodafinil is a wake-promoting agent approved in 2007 by the US Food and Drug Administration for the treatment of excessive sleepiness. A rapid, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of armodafinil in human plasma was developed and validated. Armodafinil and internal standard (armodafinil d-10) were extracted from human plasma using protein precipitation combined with liquid-liquid extraction. This developed method only requires 50 µL of plasma for the analysis. The chromatographic separation was performed with a Waters symmetry, C18 , 4.6 × 150 mm, 5 µm column using formic acid, water and acetonitrile as solvent delivered at a 0.7 mL/min flow rate. The total run time of the method was 3 min. The method was validated according to regulatory guidance in terms of specificity, selectivity, linearity, matrix effect, recovery and stability. Optimized Q1/Q3 mass transitions for armodafinil and armodafinil d-10 were 274.1/167.2 (m/z) and 284.4/177.4 (m/z) respectively. The method showed linearity within the tested concentration range of 10-10,000 ng/mL. The method was successfully applied to quantify armodafinil concentrations after single oral administration of a 250 mg tablet in a clinical study conducted in healthy volunteers. Significant advantages of this method are minimal sample volume, short run time and a lower LLOQ.

Computer tomographic analysis of organ motion caused by respiration and intraoperative pneumoperitoneum in a porcine model for navigated minimally invasive esophagectomy.

BACKGROUND: Navigation systems have the potential to facilitate intraoperative orientation and recognition of anatomical structures. Intraoperative accuracy of navigation in thoracoabdominal surgery depends on soft tissue deformation. We evaluated esophageal motion caused by respiration and pneumoperitoneum in a porcine model for minimally invasive esophagectomy. METHODS: In ten pigs (20-34 kg) under general anesthesia, gastroscopic hemoclips were applied to the cervical (CE), high (T1), middle (T2), and lower thoracic (T3) level, and to the gastroesophageal junction (GEJ) of the esophagus. Furthermore, skin markers were applied. Three-dimensional (3D) and four-dimensional (4D) computed tomography (CT) scans were acquired before and after creation of pneumoperitoneum. Marker positions and lung volumes were analyzed with open source image segmentation software. RESULTS: Respiratory motion of the esophagus was higher at T3 (7.0 ± 3.3 mm, mean ± SD) and GEJ (6.9 ± 2.8 mm) than on T2 (4.5 ± 1.8 mm), T1 (3.1 ± 1.8 mm), and CE (1.3 ± 1.1 mm). There was significant motion correlation in between the esophageal levels. T1 motion correlated with all other esophagus levels (r = 0.51, p = 0.003). Esophageal motion correlated with ventilation volume (419 ± 148 ml) on T1 (r = 0.29), T2 (r = 0.44), T3 (r = 0.54), and GEJ (r = 0.58) but not on CE (r = - 0.04). Motion correlation of the esophagus with skin markers was moderate to high for T1, T2, T3, GEJ, but not evident for CE. Pneumoperitoneum led to considerable displacement of the esophagus (8.2 ± 3.4 mm) and had a level-specific influence on respiratory motion. CONCLUSIONS: The position and motion of the esophagus was considerably influenced by respiration and creation of pneumoperitoneum. Esophageal motion correlated with respiration and skin motion. Possible compensation mechanisms for soft tissue deformation were successfully identified. The porcine model is similar to humans for respiratory esophageal motion and can thus help to develop navigation systems with compensation for soft tissue deformation.

Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight.

Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors.

The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R(1), R(2), R(3)), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 µM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R(1) position, bulky aromatic groups at the R(2) position, and benzyl group at the R(3) position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands.