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Science is constantly evolving. As a result, novel tools as well as new issues are arising for clinical pharmacologists. In this chapter, we will discuss some emerging topics in clinical pharmacology, including model-informed drug development, real-world data and real-world evidence, and digital health technologies, as well as the microbiome and its impact on drug effect and treatment outcome.

Effective treatment approaches in a pandemic such as COVID-19 hinge on expeditious identification of sound dosing strategies. Informed by experience with the Food and Drug Administration (FDA) Animal Rule, this commentary illustrates a framework for leveraging and integrating clinical pharmacology information for dose selection to treat novel infections in a public health emergency setting.

The Food and Drug Administration's (FDA's) "Animal Rule" provides a unique regulatory pathway for drugs and biologics intended to treat serious or life-threatening conditions caused by exposure to lethal or permanently disabling chemical, biological, radiological, or nuclear agents when human efficacy studies are not ethical and field trials are not feasible. Human dose selection under the Animal Rule is based on integrating the totality of clinical pharmacology evidence collected in in vitro, animal, and human studies. This review discusses the necessary pharmacokinetic and pharmacodynamic information and methods for determining the effective human dose of antimicrobials under the Animal Rule and presents case studies illustrating the utility of a totality of evidence approach for different methods.

Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro 50%/90% maximal effective concentration values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.

Development of effective medical countermeasures for biodefense is vital to United States biopreparedness and response in the age of terrorism, both foreign and domestic. A traditional drug development pathway toward approval is not possible for most biodefense-related indications, creating the need for alternative development pathways such as the FDA's Animal Rule. Under this unique regulatory mechanism, FDA-approval is based on adequate and well-controlled animal studies when it is neither ethical nor feasible to conduct human efficacy studies. Translation of animal efficacy findings to humans is accomplished by use of modeling and simulation techniques. Pharmacokinetic and exposure-response modeling allow effective dosing regimens in humans to be identified, which are expected to produce similar benefit to that observed in animal models of disease. In this review, the role of modeling and simulation in determining the human dose for biodefense products developed under the Food and Drug Administration's Animal Rule regulatory pathway is discussed, and case studies illustrating the utility of modeling and simulation in this area of development are presented.

Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate.

Progressive vaccinia (PV) is a rare but potentially lethal complication that develops in smallpox vaccine recipients with severely impaired cellular immunity. We describe a patient with PV who required treatment with vaccinia immune globulin and who received 2 investigational agents, ST-246 and CMX001. We describe the various molecular, pharmacokinetic, and immunologic studies that provided guidance to escalate and then successfully discontinue therapy. Despite development of resistance to ST-246 during treatment, the patient had resolution of PV. This case demonstrates the need for continued development of novel anti-orthopoxvirus pharmaceuticals and the importance of both intensive and timely clinical and laboratory support in management of PV.

Drug development for emerging infections offers challenges in translational pharmacology. For drugs and biologics for which adequate and well-controlled efficacy studies in humans cannot be ethically conducted or are not feasible, as would be the case with many emerging infections, translation of preclinical information to humans is the cornerstone of drug development. This article focuses on the role of the clinical pharmacologist in translating pharmacology information to support approval of new agents for emerging infections, under the US Food and Drug Administration's (FDA's) Animal Rule. Clinical Pharmacology & Therapeutics (2009); 86 3, 328–331. doi:10.1038/clpt.2009.106

Development of drugs and biologics for which adequate and well-controlled efficacy studies in humans cannot be ethically conducted or are not feasible poses significant challenges. For these agents, clinical pharmacology information is used to translate preclinical efficacy findings to humans and is a cornerstone that supports a human dose. This article focuses on the role of clinical pharmacology in determining the human dose for new drugs and biologics under the Animal Rule regulatory pathway.

Glioblastoma (GBM) cells are highly invasive and respond poorly to radiation and chemotherapy. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase signals through protein complexes mTORC1 and mTORC2 to regulate several essential processes such as cell growth, proliferation, metabolism, survival, and autophagy. mTOR is activated by oncogenic signaling, including PI3K which is frequently deregulated in high grade glioma. Using GBM patient-derived neurospheres and xenograft tumors (PDX), we have tested CC-223 (Celgene), an ATP-competitive TOR kinase inhibitor (TORKi), and CC-115 (Celgene), a dual TORK/ DNA-PK inhibitor. The latter is also an attractive drug target because of its role in the repair of double stranded DNA breaks, conferring resistance to radiation and temozolomide (TMZ), used in the standard of care for GBMs. Neurospheres enriched in cancer stem cells (CSCs) were cultured from freshly resected GBM tumors. Dose-response curves for both compounds were obtained for nine GBM neurosphere lines, resulting in stratification into sensitive and resistant groups. CC-115 single agent presented higher efficacy than CC-223 for all GBM CSC lines. Sensitivity to TORKi was not correlated with PTEN status in this sample set. To investigate the changes in CSC signaling pathways in response to TORK/DNA-PK inhibition, CC-115 dose-dependent changes in the levels of 70 proteins and phosphoproteins in 4 CSC lines presenting variable sensitivities were determined by reverse phase protein arrays (RPPA) The levels of p-mTOR, several downstream targets of both mTORC1 (e.g. p-S6K, p-4EBP1, p-RPS6K) and mTORC2 (p-AKT), and cyclin B1 were decreased in response to CC-115 IC30 dose in all CSC lines. Four CSC lines from the CC-115 sensitive group were implanted intracranially in nude mice. PDXs were administered CC-115 (2.5 - 5mg/kg) and CC-223 (10mg/kg), or vehicle control 5 days/week by oral gavage (n>7/group) for a minimum of 4 weeks. CC-115 monotherapy significantly increased survival of one PDX line. Combination therapy significantly increased survival of GBM PDX lines that did not respond to either CC-115 or TMZ monotherapy. Toxicity associated with CC-115 treatment in nude mice prevented a dose-escalation study. We conclude that the TORK/DNA-PK inhibitor CC-115 is a promising targeted therapy for GBMs, particularly in combination with DNA-targeting treatments. Our results underline the molecular diversity in GBMs reflected in the variable chemosensitivity, and the need to stratify patients for targeted therapies to increase the chance of success. Citation Format: Kimberly Bergman, Susan M. Irtenkauf, Laura A. Hasselbach, Claudius Mueller, Emanuel Petricoin, Heather Raymon, Tom Mikkelsen, Ana C. Decarvalho. TORK/DNA-PK inhibitor CC-115 is effective as a single agent in a subset of glioblastoma patient-derived cancer stem cells and xenografts and potentiates temozolomide therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1755. doi:10.1158/1538-7445.AM2015-1755