Clinical Pharmacology of RNA Interference-Based Therapeutics: A Summary Based on Food and Drug Administration-Approved Small Interfering RNAs.

RNA-based oligonucleotide therapeutics are revolutionizing drug development for disease treatment. This class of therapeutics differs from small molecules and protein therapeutics in various ways, including both its mechanism of action and clinical pharmacology characteristics. These unique characteristics, along with evolving oligonucleotide-associated conjugates allowing specific tissue targeting, have fueled interest in the evaluation of RNA-based oligonucleotide therapeutics in a rapidly increasing number of therapeutic areas. With these unique attributes as well as growing therapeutic potential, oligonucleotide therapeutics have generated significant interest from a clinical pharmacology perspective. The Food and Drug Administration (FDA) previously published results of a survey that summarized clinical pharmacology studies supporting oligonucleotide therapies approved and in development between 2012 and 2018. Since the first approval of a small interfering RNA (siRNA) therapeutic in 2018, this class of modalities has gained momentum in various therapeutic areas. Hence, a comprehensive examination of the clinical pharmacology of FDA-approved siRNA therapeutics would benefit the path forward for many stakeholders. Thus, in this current review, we thoroughly examine and summarize clinical pharmacology data of the FDA-approved siRNA therapeutics approved from 2018 (year of first approval) to 2022, aimed at facilitating future drug development and regulatory decision making. SIGNIFICANCE STATEMENT: This review systematically summarizes the clinical pharmacology information of Food and Drug Administration (FDA)-approved small interfering RNAs (siRNA) therapeutics. SiRNAs are revolutionizing the drug development field. Unique clinical pharmacology characteristics represent a differentiating factor for this class of therapeutics. The FDArecently published a draft guidance for clinical pharmacology considerations for developing oligonucleotide therapeutics. As clinical development of this class of therapeutics is fast growing, this review will inform discovery and clinical-stage evaluation of upcoming siRNA-associated drug candidates.

Breaking Down Barriers to Effective Patient Care.

The theme for the 2018 ASCPT Annual Meeting is "Breaking Down Barriers to Effective Patient Care." This theme refers to the essential contributions of clinical pharmacology to the development of today's discovery into tomorrow's medicine. The various subdisciplines within clinical pharmacology serve to move molecules through the various stages of drug development and also refine or expand use of the drug postapproval. The wide range of topics covered by the 2018 Annual Meeting scientific program demonstrates the breadth of clinical pharmacology's impact. Because of new methods being developed to identify drug targets, medicines are being developed for patients with rare diseases. Biomarkers and diagnostic tools are advancing the development of drugs for neurodegenerative disorders, cancer, and many other diseases. Preclinical data are playing a key role in informing the quantitative clinical pharmacology of drugs, especially antimicrobials, and animal efficacy data are pivotal for drugs that are developed and approved under the animal rule. The use of pharmacogenomics, model-based drug development, informatics, and identification and evaluation of subgroups are key topics. With our focus on the patient, the Annual Meeting, and this issue of Clinical Pharmacology & Therapeutics, will highlight the many innovative ways that current clinical pharmacology investigations are attempting to dissolve barriers to effective patient care.

A regulatory perspective on the role of drug interactions in antiretroviral drug development.

PURPOSE OF REVIEW: To provide a regulatory perspective on the role of drug interaction information in the development of antiretroviral drugs. Additionally, this review highlights novel studies that provided important information for the safe and effective use of antiretroviral medications. The management of drug interactions in HIV therapy becomes more complex with the introduction of each new drug because many antiretroviral drugs are involved in multiple metabolic and transporter-based interactions. Therefore, a comprehensive preclinical evaluation to characterize a new drug's metabolic pathway(s) followed by in-vivo studies is critical for the safe use of combination antiretroviral therapy. RECENT FINDINGS: This review highlights published studies to illustrate several clinical and regulatory issues for in-vivo drug interaction studies such as general design issues, study-population selection, study-design options, use of historical controls and interpretation of results. SUMMARY: Early identification of potential drug interactions can help identify and prioritize clinically important interaction studies essential to the overall development process. Understanding the clinical implications and management of drug interactions can lead to more effective long-term therapy, reduce toxicity, and delay the development of resistance.