Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice.

INTRODUCTION: Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible. METHODS: Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality-edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges. RESULTS: Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aß42 and the plasma Aß42/ Aß40 ratio-fluid biomarkers to detect central amyloid negativity-is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period. DISCUSSION: This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

Fatal Case of Exercise Collapse Associated with Sickle Cell Trait with Novel Underlying LAMA2 Mutation.

ABSTRACT: Sickle cell trait is typically thought to be an asymptomatic carrier state, but it is rarely associated with exertional rhabdomyolysis in cases termed Exercise Collapse Associated with Sickle Cell Trait (ECAST). In a subset of these cases, underlying disease contributes to the development and/or severity of the ensuing medical complications. We describe the first ever case of ECAST reported in a previously asymptomatic, multiply deployed, highly physically active service member with an underlying heterozygous LAMA2 mutation. Moreover, the mutation identified via whole exome sequencing is a novel, likely pathogenic variant that has yet to be described in the literature.

3D reconstruction of skin and spatial mapping of immune cell density, vascular distance and effects of sun exposure and aging.

Mapping the human body at single cell resolution in three dimensions (3D) is important for understanding cellular interactions in context of tissue and organ organization. 2D spatial cell analysis in a single tissue section may be limited by cell numbers and histology. Here we show a workflow for 3D reconstruction of multiplexed sequential tissue sections: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis). We demonstrate MATRICS-A in 26 serial sections of fixed skin (stained with 18 biomarkers) from 12 donors aged between 32-72 years. Comparing the 3D reconstructed cellular data with the 2D data, we show significantly shorter distances between immune cells and vascular endothelial cells (56 µm in 3D vs 108 µm in 2D). We also show 10-70% more T cells (total) within 30 µm of a neighboring T helper cell in 3D vs 2D. Distances of p53, DDB2 and Ki67 positive cells to the skin surface were consistent across all ages/sun exposure and largely localized to the lower stratum basale layer of the epidermis. MATRICS-A provides a framework for analysis of 3D spatial cell relationships in healthy and aging organs and could be further extended to diseased organs.

Protecting Privacy: Health Insurance Portability and Accountability Act of 1996, Twenty-First Century Cures Act, and Social Media.

Advances in electronic health record technology, the ever-expanding use of social media, and cybersecurity sabotage threaten patient privacy and render physicians and health care organizations liable for violating federal and state laws. Violating a patient's privacy is both an ethical and legal breach with potentially serious legal and reputational consequences. Even an unintentional Health Insurance Portability and Accountability Act of 1996 (HIPAA) violation can result in financial penalties and reputational harm. Staying complaint with HIPAA requires vigilance on the part of both individuals with legitimate access to protected health information (PHI) and the organizations handling that PHI.

False Claims Act and Anti-Kickback Statute: Avoiding Legal Landmines.

Health care entities doing business with the federal government may run afoul of the False Claims Act and Anti-Kickback Statute not only when they directly submit fraudulent claims for government reimbursement but also when they create schemes that manipulate others into submitting (whether knowingly or unknowingly) illegal claims. In recent years, the Department of Justice is deploying these statutes to ensure that electronic health records are built and maintained with appropriate cybersecurity protections.

Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates.

Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.

A combined physiologically-based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease.

Antibody-mediated removal of aggregated ß-amyloid (Aß) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aß monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aß40 and Aß42 aggregation and clearance of aggregated Aß by activated microglia cells, which is enhanced by the interaction of antibody-bound Aß. The model allows for the prediction of Aß positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aß42 and plasma Aß42 /Aß40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aß42 /Aß40 ratio while slightly overestimating the change in CSF Aß42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

Learn-confirm in model-informed drug development: Assessing an immunogenicity quantitative systems pharmacology platform.

Immunogenicity against therapeutic proteins frequently causes attrition owing to its potential impact on pharmacokinetics, pharmacodynamics, efficacy, and safety. Predicting immunogenicity is complex because of its multifactorial drivers, including compound properties, subject characteristics, and treatment parameters. To integrate these, the Immunogenicity Simulator was developed using published, predominantly late-stage trial data from 15 therapeutic proteins. This single-blinded evaluation with subject-level data from 10 further monoclonals assesses the Immunogenicity Simulator's credibility for application during the drug development process.

Application of physiologically based pharmacokinetic models for therapeutic proteins and other novel modalities.

The past two decades have seen diversification of drug development pipelines and approvals from traditional small molecule therapies to alternative modalities including monoclonal antibodies, engineered proteins, antibody drug conjugates (ADCs), oligonucleotides and gene therapies. At the same time, physiologically based pharmacokinetic (PBPK) models for small molecules have seen increased industry and regulatory acceptance.This review focusses on the current status of the application of PBPK models to these newer modalities and give a perspective on the successes, challenges and future directions of this field.There is greatest experience in the development of PBPK models for therapeutic proteins, and PBPK models for ADCs benefit from prior experience for both therapeutic proteins and small molecules. For other modalities, the application of PBPK models is in its infancy.Challenges are discussed and a common theme is lack of availability of physiological and experimental data to characterise systems and drug parameters to enable a priori prediction of pharmacokinetics. Furthermore, sufficient clinical data are required to build confidence in developed models.The PBPK modelling approach provides a quantitative framework for integrating knowledge and data from multiple sources and can be built on as more data becomes available.

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.

The clinical impact of therapeutic interventions in Parkinson's disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion channel effector proteins based on experimentally observed intracellular signaling. The calculated beta/gamma (b/g) power spectrum of the local field potentials in the subthalamic nucleus was previously calibrated on the clinically relevant Unified Parkinson's Disease Rating Scale (UPDRS). When combining this QSP model with PK modeling of different formulations of L-DOPA, we calculated the b/g fluctuations over a 16 h awake period and used a weighted distance from a specific threshold to determine the cumulative liability of OFF-Time. Prediction of OFF-time with clinical observations of different L-DOPA formulations showed a significant correlation. Simulations show that augmentation with the adenosine A2A antagonist preladenant reduces OFF-time with 6 min for carbidopa/levodopa 950 mg 5-times daily to 37 min for 100 mg L-DOPA - 3 or 5 times daily. Exploring delays between preladenant and L-DOPA intake did not improve the outcome. Hypothetical A2A antagonists with an ideal PK and pharmacology profile can achieve OFF-Time reductions ranging from 9.5 min with DuoDopa to 55 min with low dose L-DOPA formulations. Combination of the QSP model with PK modeling can predict the anticipated OFF-Time reduction of novel A2A antagonists with standard of care. With the large number of GPCR in the model, this combination can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice.

COVID-19 nightmare response and stress: A new Mexico sample based survey.

Studies conducted during the COVID-19 Pandemic have reported increased rates of mental illnesses including depression, anxiety, and post-traumatic stress disorder (PTSD) [1]. A common symptom of mental illness is change in Rapid Eye Movement (REM) sleep, the phase of sleep associated with dreaming and nightmares. The COVID-19 pandemic offers a unique opportunity to evaluate the effects of systemic stress on nightmares. In this study, we investigate whether the COVID-19 pandemic affects nightmare frequency and content using a web-based survey within the state of New Mexico. The survey returned 197 responses showing an increase in the quantity of both bad dreams and nightmares. Furthermore, significant changes in nightmare themes were reported compared to relative rates prior to the pandemic (RR 1,42, p < 0.01; RR 5, p < 0.001). This novel data supports that increased stress from the COVID-19 pandemic has altered dream and nightmare content and frequency.

The Medicolegal and Ethical Dimensions of Physician Prescription Reluctance.

ABSTRACT: This article addresses the potential legal ramifications for neurologists caring for patients with Alzheimer disease (AD) who elect neither to prescribe aducanumab nor to refer patients with AD for treatment with aducanumab. To prevail against a neurologist for failing to prescribe aducanumab or refer for aducanumab treatment, the plaintiff would have to establish that the neurologist's failure to prescribe the medication or refer for treatment was a breach of the standard of care. The standard of care is conceptualized as the generally accepted approach to diagnosing or treating a condition. However, the controversy surrounding the US Food and Drug Administration's (FDA's) approval process for aducanumab (which was based on the drug's efficacy at reducing brain amyloidosis rather than on clinically meaningful efficacy) as well as the American Academy of Neurology (AAN) position statement on aducanumab and the recent decision by the Centers for Medicare & Medicaid Services (CMS) to limit Medicare coverage of the drug and its associated costs to patients enrolled in qualifying clinical trials indicate that aducanumab cannot yet be considered the standard of care for the treatment of AD. Although deciding not to prescribe aducanumab does not violate the standard of care, neurologists treating patients with AD and not recommending this treatment should explain to their patients and their patients' surrogate decision makers why they are not recommending the treatment.

Legal and Ethical Challenges in the Care of the Pregnant Patient After Brain Death.

ABSTRACT: Using two scenarios based on real-life cases reported in the media, this article examines the ethical and legal controversies that arise when a pregnant woman dies based on neurologic criteria while her fetus remains alive. In the first scenario, all parties agreed to maintain physiologic support until a safe delivery could be achieved, whereas in the second scenario the woman's family sought a legal remedy to stop the hospital from continuing to provide physiologic support for the patient and her neurologically devastated fetus.

Interprofessional Internet Consultations: The Potential Benefits and Perils of eConsults.

ABSTRACT: This article addresses the question of whether neurologists performing interprofessional internet consultations, known as eConsults, face the same malpractice liability as for face-to-face patient care. Because the physician-patient relationship is usually unambiguous, determining the scope of legal liability arising from these relatively new approaches to patient care requires understanding the types of interactions courts have found to establish a patient-physician relationship.

False Claims Act Overview and Implications for Neurologists.

ABSTRACT: The US Department of Health and Human Services Office of the Inspector General identifies the five most important federal fraud and abuse laws that are most applicable to physicians: the False Claims Act, the Anti-Kickback Statute, the Physician Self-Referral Law (Stark Law), the Exclusion Authorities, and the Civil Monetary Penalties LawThe False Claims Act is the US government's primary tool for combating fraud perpetrated through the filing of false claims for federal government reimbursement. Neurologists and companies serving the needs of neurologic patients have not been immune from False Claims Act-related legal action. This article provides an overview of the False Claims Act, uses real-life neurologic cases to illustrate the range of False Claims Act violations and recoveries, and offers some practical compliance suggestions.

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets.

BACKGROUND: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (Tmax) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another. OBJECTIVES: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant "safe space" for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the "safe space" for dissolution. METHODS: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy. RESULTS: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the "safe space" based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem. CONCLUSIONS: A PBPK/PD model indicates that current BCS-biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.

Criminal Culpability for Acts Committed During a Possible Episode of REM Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) may result in a patient injuring a bed partner while acting out a dream. This article examines the complexities associated with RBD as a criminal defense strategy as well as the legal implications for physicians and their duty to patients and their families to mitigate risks associated with possible injuries related to RBD.

Legal Liability Associated With rtPA Administration and Surrogate Decision Makers.

Stroke is one of the most common conditions neurologists treat in emergency situations. This article examines the issues of surrogate decision makers and the physician's potential legal liability in the context of the administration or nonadministration of recombinant tissue plasminogen activator (rtPA) in a common emergency department scenario.

Liability and Failure to Warn a Patient.

This medicolegal article examines a physician's liability when he or she has knowledge of adverse effects associated with a prescription medication and suggests ways to mitigate that liability risk. The article also discusses the circumstances under which pharmaceutical companies face liability for side effects such as tardive dyskinesia.

Driving and Epilepsy: Ethical, Legal, and Health Care Policy Challenges.

Although the principle of autonomy allows patients to refuse interventions their physicians recommend, patients are not free to ignore legally mandated restrictions on driving, and physicians are ethically justified in constraining their patients' driving rights in compliance with state law. Furthermore, the standard of care for treatment of patients with epilepsy includes counseling about lifestyle modifications that promote patient safety and compliance with the law. Neurologists should not only counsel their patients with epilepsy about legally mandated driving restrictions but also document this counseling in the medical record. Failure to counsel and to document may result in legal liability if patients experience seizures while driving and injure either themselves or third parties. The neurologist's duty of care may be limited to the patient in some jurisdictions but may be extended to injured third parties in others. Furthermore, a patient's own contributory negligence may limit or completely foreclose recovery against the physician to varying degrees, depending on the state in which the injury occurred.