Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers.

In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves "dose-finding" studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases.

Clinical pharmacology considerations for first-in-human clinical trials for enzyme replacement therapy.

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023.

Dose selection for biological enzyme replacement therapy indicated for inborn errors of metabolism.

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial.

Impact of Organ Impairment on the Pharmacokinetics of Therapeutic Peptides and Proteins.

The kidneys and liver are major organs involved in eliminating small-molecule drugs from the body. Characterization of the effects of renal impairment (RI) and hepatic impairment (HI) on pharmacokinetics (PK) have informed dosing in patients with these organ impairments. However, the knowledge about the impact of organ impairment on therapeutic peptides and proteins is still evolving.

A Magic Trick Training Program to Improve Social Skills and Self-Esteem in Adolescents With Autism Spectrum Disorder.

Importance: Low social competence is one of the most complex and resistant challenges faced by adolescents with autism spectrum disorder (ASD). Occupational therapy practitioners have recognized the potential benefits of using the arts, including training in magic tricks, as a therapeutic medium to improve and enhance clients' psychosocial well-being.

Objective: To describe the efficacy of a virtual magic trick training program (MTTP) to enhance social skills and self-esteem in adolescents with ASD.

The feasibility and preliminary effects of a pilot randomized controlled trial: Videoconferencing acceptance and commitment therapy in distressed family caregivers of people with dementia.

This pilot randomized controlled trial (RCT) examined preliminary effects of an 8-week videoconferencing acceptance and commitment therapy (ACT) program supplemented with psychoeducation materials on distressed family caregivers of persons living with dementia (PLWD) compared to the control group provided with psychoeducation materials only. Nineteen family caregivers of PLWD in the USA were randomly assigned to the ACT group or the control group. Data was collected at pretest, posttest, and 1-month follow-up (F/U).

Physiologically Based Pharmacokinetic Modeling of Metformin in Children and Adolescents With Obesity.

Childhood obesity continues to rise in the United States and, with it, the off-label use of metformin for weight loss. The influence of age and obesity on the drug's disposition and exposure has not previously been studied using a mechanistic framework. Here, an adult physiologically based pharmacokinetic (PBPK) model of metformin was scaled to pediatric populations without obesity, with overweight/obesity, and with severe obesity; a published virtual population of children and adolescents with obesity was leveraged during model evaluation.

Acceptance and Commitment Therapy (ACT) Guided Online for Distressed Caregivers of Persons Living with Dementia.

Objectives: This study examined the effects of a guided online acceptance and commitment therapy (ACT) intervention on distressed family caregivers of persons living with dementia and explored the experiences of these caregivers in the ACT intervention.

Methods: Seven family caregivers experiencing psychological distress individually participated in 10 ACT videoconference sessions guided by a trained coach. Quantitative data, such as psychological distress, burden, and ACT processes, were collected at pretest and posttest and analyzed using the Wilcoxon signed-rank test.

The 'magic' of magic camp from the perspective of children with hemiparesis.

Previous studies have examined the quantitative results of using an organized approach of teaching and learning magic tricks-a therapeutic magic camp-but set aside the qualitative aspect. The purpose of this qualitative study is to explore the interpretation of the lived experience of children with hemiparesis after they have participated in a therapeutic magic camp. Six children, aged between 11 and 14 years old, with hemiparesis who completed the magic camp program 3 months prior were invited to participate in an in-person individual semistructured interview.