CLINICAL PHARMACOKINETICS AND SAFETY TRIALS IN DOWN SYNDROME

Duke University, Durham NC

Investigators

Abstract

Background and Significance: Down syndrome is a condition in which a person is born with an extra copy of chromosome 21. The condition is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia), particularly in infancy. People with Down syndrome may have a variety of birth defects; about half of all affected children are born with a heart defect, and some also have intestinal atresias. Individuals with Down syndrome have an increased risk of developing several medical conditions, including childhood leukemias, hearing and vision problems, gastroesophageal reflux, diabetes, obesity, hypothyroidism, and celiac disease. The rate of Attention Deficit/Hyperactivity Disorder (ADHD) is three to five times higher than in the general population, and other neurological conditions such as seizures, autism, and behavioral problems are also more common in those with Down syndrome. Individuals with Down syndrome have an increased risk of infections such as pneumonia, due in part to immunological differences, airway anatomical factors, and comorbidities such as heart defects and pulmonary hypertension. About half of adults with Down syndrome develop Alzheimer?s Disease (AD), and the risk increases with advancing age (generally starting around the mid-50s or later). At the same time, people with Down syndrome are ?protected? from other common conditions in the adult population, such as hypertension, coronary artery disease, and most forms of solid tumors such as breast cancer. Despite increases in lifespan among individuals with Down syndrome, opportunities for them to participate in medication trials have been hampered by difficulties in recruiting large enough clinical cohorts, limited knowledge of appropriate endpoints and outcome measures for this population, lack of stratification to identify positive responses to medications above placebo effects, and lack of resources to sustain a clinical trials program for the long-term that would allow new therapeutics to be tested. One of the potential barriers to drug development trials for drugs to be used by people with Down syndrome is the limited and/or lack of knowledge of how these individuals may metabolize drugs, including basic knowledge about pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenomics (PGx) in Down syndrome populations. For example, children with Down syndrome require lower doses of cytotoxic drugs to treat their leukemia. NIH?s new INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) project may help to address some of these questions. The project is a comprehensive, trans-NIH strategy to address critical health and quality-of-life needs for individuals with Down syndrome. The main goals of the INCLUDE project are: to support clinical trials on conditions and diseases that disproportionately affect people with Down syndrome, both to accelerate the development of new therapies tailored to their physiology; as well as include individuals with Down syndrome in ongoing clinical trials. A separate activity under the auspices of the National Institute on Aging is providing clinical trials infrastructure to studies of anti-AD therapeutics in Down syndrome. A patient registry known as DS-Connect® is supported by NICHD and has been used to recruit for clinical research studies and clinical trials (https://DSConnect.nih.gov). The Best Pharmaceutical for Children Act (BPCA) Pediatric Trials Network (PTN) is strategically poised to address the NICHD?s goals of including participants with Down syndrome in new or ongoing clinical trials through existing clinical trials networks. The purpose of this task order is to leverage the infrastructure of the PTN to provide an additional platform for the inclusion of individuals with Down syndrome into pharmacology-based clinical trials conducted under the BPCA Clinical Program. Scope and Scientific Rationale The primary goal of this task order is to recruit this patient population into the PTN Opportunistic study model. The Opportunistic study design involves the study of dosing and safety of multiple medications prescribed by physicians to their patients. The research will be to determine if the doses of medications given to individuals with Down syndrome are appropriate and safe. A second goal, to be interwoven with the first, is to develop a training program for clinical researchers, both within the PTN and including experts in conducting research in Down syndrome, that will provide bi-directional guidance in trial design, recruitment, and engagement specifically in this population. The purpose of a clinical study is to characterize the PK, PD, and PGx of understudied off-patent drugs administered to children and potentially young adults (ages 18-25 years) with Down syndrome who are receiving drugs per standard of care as prescribed by their treating caregiver. In order to understand drug disposition and metabolism, biological samples will be collected from participants. The opportunistic design of this study will allow for a minimal risk study, an expanded enrollment net, evaluation of off-patent drugs, and capitalization on procedures performed per standard of care to maximize study efficiency and data collection and minimize potential harm to participants. The data collected through this initiative will provide valuable PK, dosing, and safety information for drugs used in this population.