Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

Patient involvement in relative effectiveness assessments in the European Network for Health Technology Assessment

Patient involvement in the process of producing health technology assessments has become increasingly important. In the European Network for Health Technology Assessment (EUnetHTA), several approaches to patient involvement were explored. The outcome was a document on “Patient Input in Relative Effectiveness Assessments” that is available for access and was published in 2019. The aim of this article is to analyze the experience gained by EUnetHTA in patient involvement for EUnetHTA assessment production, describe and quantify the approaches used, and outline the challenges and avenues for the improvement of current processes. Patients were involved in twenty-three of thirty-six pharmaceutical and other technology EUnetHTA assessments from June 2016 until the end of November 2019. Approaches to patient involvement included using a patient input template, one-on-one conversations, group conversations, scoping meeting with patients, and other approaches. Although it is recognized that patient involvement is important to understand the needs of the target patient population, challenges remain with timely patient involvement. Additionally, further efforts are needed to guide assessment teams on how to implement and enhance the visibility of patient input in assessments.

Developing a metformin prescribing tool for use in adults with mental illness to reduce medication-related weight gain and cardiovascular risk

Objectives: There is considerable evidence that metformin reduces weight gain associated with antipsychotic medication. The aim of this study was to develop an easy-to-use metformin prescribing tool in order to enable clinicians to prescribe metformin safely and confidently. Methods: The authors undertook a survey of clinicians and reviewed the published literature and existing guidelines concerning the use of metformin to reduce weight gain in adults with mental illness. Results: A metformin prescribing tool was devised based on the literature, national cardiovascular and diabetes guidelines and Australian metformin prescribing recommendations. The metformin prescribing tool guides clinicians through the considerations required for appropriate selection of the target patient population and safe prescription of metformin. Conclusions: A novel, easy-to-use, one-page reference has been developed for busy clinicians that can be laminated and displayed in consulting rooms and psychiatric inpatient units to address weight gain and obesity associated with antipsychotic medications in people with mental illness.

In Vitro DEXA-BMD Measurements Affected by Type of Soft Tissue Surrogate

Dual-energy x-ray absorptiometry (DEXA), the technique most widely used to assess skeletal integrity, is routinely performed on cadaveric tissue to ensure that the bone mineral densities (BMD) of the test specimens are representative of the target patient population for a particular orthopaedic device [1]. It is well established that DEXA-BMD measurements are sensitive to the amount of fat and other soft tissue present in the region of interest [2]. Recognizing that the removal of perivertebral soft tissue may affect DEXA-BMD readings of in vitro cadaveric specimens, biomechanics researchers have used various “torso surrogates” to simulate the removed tissue and x-ray attenuation. These include: 1) submersion of spinal sections in a physiological saline bath, 2) surrounding spinal sections with gel-filled packs, and 3) packing rice-filled bags around spinal sections and within the internal cavity of eviscerated torsos [3, 4]. It is unknown whether these inter-study differences in technique affect in vitro DEXA measurements. Given the prevalence of soft tissue artifacts in vivo, the goal of this study is to examine the sensitivity of in vitro DEXA-BMD to the quantity and composition of soft tissue surrogates. This work is the first step in a broader study to develop a set of best practices for DEXA scanning of cadaveric tissue.