Antimicrobial Dose Selection under the Animal Rule.

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.

Connecting Hydroxychloroquine In Vitro Antiviral Activity to In Vivo Concentration for Prediction of Antiviral Effect: A Critical Step in Treating Patients With Coronavirus Disease 2019.

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.

Modeling and simulation in dose determination for biodefense products approved under the FDA animal rule.

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.

Designing drug trials: considerations for pregnant women.

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: case description and laboratory-guided therapy with vaccinia immune globulin, ST-246, and CMX001.

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.

Omeprozole therapy in pediatric patients after liver and intestinal transplantation.

BACKGROUND: Proton pump inhibitors such as omeprazole are increasingly used to prevent stress-related gastric bleeding in critically ill patients. In this investigation, the acid-suppressive potency of omeprazole was assessed in one at-risk group, pediatric patients undergoing liver or intestinal transplantation, or both. METHODS: Twenty-two patients ranging in age from 0.9 to 108 months (23.8 +/- 6.5) underwent isolated liver (n = 10) or intestinal (11 with composite liver allografts) transplantation. Omeprazole was delivered in bicarbonate suspension through a nasogastric tube. Therapy was started after surgery at 0.5 mg/kg every 12 hours. Gastric pH monitoring was performed approximately 2 days later. RESULTS: For the entire group, mean gastric pH equaled 6.1 +/- 0.3, the same in recipients of isolated liver and intestinal allografts. Twelve of the 22 patients demonstrated a discontinuous omeprazole effect, that is, dissipation of acid reduction before the next dose. Five of the 12 patients with discontinuous omeprazole effect had mean gastric pH of less than 5 (3.9 +/- 0.4). In 4 of these 5, the omeprazole dosing interval was shortened to every 8 or every 6 hours, resulting in an increase in mean pH to 6.6 +/- 0.2 ( P < 0.01). In the remaining 10 of 22 patients, acid suppression was uninterrupted until the next dose. No patient experienced bleeding attributable to gastric erosion. CONCLUSION: Omeprazole suspended in sodium bicarbonate is an effective acid-suppressing agent in pediatric recipients of liver or intestinal transplant, or both. A dosage of 0.5 mg/kg every 12 hours is sufficient for most patients, but dosing every 6 to 8 hours is required to assure maximal acid suppression in all.