Accrediting bodies for Doctor of Pharmacy (Pharm.D.) and postgraduate residency training programs recognize the importance of research and scholarship training. However, specific guidance on how research and scholarship fundamentals should be delivered to trainees has not been provided. As a result, competing priorities often create barriers for trainees to develop research and scholarship skills and limit the trainees' ability to conduct and participate in high‐quality, meaningful research experiences. The purpose of this “how‐to” guide is to assist pharmacy school faculty and pharmacy residency program directors with strategies to overcome programmatic, trainee, and project barriers to providing a high‐quality training experience in research and scholarship. Programmatic topics addressed include institutional support and program oversight, expertise and number of research mentors, incentives for mentor engagement, and competing priorities that diminish time for research activities. Trainee topics include lack of trainee interest in the assigned project, trainee departure prior to project completion, lack of knowledge of the publication process, and time constraints to work on the project. Project topics addressed include time needed to initiate a project, training on methodology relevant to a project, selection of projects that lack rigor, depth, or feasibility, and resource constraints to disseminate project results. A summary of specific recommended actions is provided to effectively overcome these common barriers encountered in research and scholarship training programs.
Despite development of modern antiretrovirals with lower drug interaction potential than their predecessors, drug interaction challenges remain. Standard treatment regimens still require multiple antiretrovirals that may cause, or may be the target of, drug interactions. Additionally, people living with HIV are living longer and often present with comorbid conditions that require concomitant long-term drug therapy. Also, treatment of infectious diseases in resource-limited settings can result in significant interactions. In this review, we describe absorption, distribution, metabolism, and excretion pathways as they relate to relevant drug interactions with antiretrovirals along with the potential clinical consequences of these interactions. We highlight clinical data that illustrate pertinent interactions and provide tools to assist in predicting drug interactions in the absence of clinical data. Given these tools and thoughtful consideration of drug combinations, drug therapy in people living with HIV can be safely and effectively managed throughout their lifetime.Understanding, predicting, and managing antiretroviral drugdrug interactions (DDIs) has traditionally been a challenge for both drug developers and clinicians treating people living with HIV (PLWH). Of more than 20 antiretrovirals developed to date, most are lipophilic in nature. Lipophilic compounds generally have higher cellular permeability and greater affinity for cytochrome P450 (CYP) drug-metabolizing enzymes and efflux drug transporters. Since these enzymes and transporters concentrate in the gastrointestinal tract and liver, most drug interactions occur at these sites. New antiretroviral (ARV) therapies bypassing CYP metabolism and drug transport have alleviated some drug interaction concerns but challenges remain. In particular, because PLWH are living longer due to effective ARV therapy, they are developing age-related comorbidities, with increasing DDI potential of polypharmacy for cardiovascular, endocrine, and oncologic disorders. In addition to bone marrow transplants for leukemia and lymphomas, the availability of solid organ transplant in PLWH can pose a DDI challenge with medications used to prevent rejection and prophylax against opportunistic infections. Finally, the introduction of new and novel ARV therapies may lag in resource-limited settings, where most of the burden of HIV exists and where other infections such as malaria and tuberculosis need to be treated or prophylaxed. This review highlights interactions between ARVs themselves and interactions between ARVs and common classes of concomitant medications. We review the relevant absorption, distribution, metabolism, and excretion pathways for these medications, the clinical consequences of administering concomitant medications with ARVs, key clinical examples of interactions where ARVs are affected by other drugs (otherwise known as the "victim" drug) or are the agent affecting concomitant drugs (otherwise known as the "perpetrator" drug), and investigate how ARV interactions...
During the past decade, the incidence and severity of Clostridium difficile infection (CDI) have significantly increased, leading to a rise in CDI-associated hospitalizations, health care costs, and mortality. Although treatment options exist for CDI, recurrence is frequent following treatment. Furthermore, patients with at least one CDI recurrence are at an increased risk of developing additional recurrences. A novel approach to the prevention of recurrent CDI is the use of monoclonal antibodies directed against the toxins responsible for CDI as an adjunct to antibiotic treatment. Bezlotoxumab, a human monoclonal antibody that binds and neutralizes C. difficile toxin B, is the first therapeutic agent to receive United States Food and Drug Administration approval for the prevention of CDI recurrence. Clinical studies have demonstrated superior efficacy of bezlotoxumab in adults receiving antibiotic therapy for CDI compared with antibiotic therapy alone for the prevention of CDI recurrence. Bezlotoxumab was well tolerated in clinical trials, with the most common adverse effects being nausea, vomiting, fatigue, pyrexia, headache, and diarrhea. The demonstrated efficacy, safety, and characteristics of bezlotoxumab present an advance in prevention of CDI recurrence.
For HIV cure strategies like “kick and kill” to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs. These results have implications for interpreting HIV treatment, prevention, or cure interventions between preclinical and clinical models.
Adequate antiretroviral (ARV) concentrations in lymphoid tissues are critical for optimal antiretroviral therapy. While the spleen contains 25% of the body's lymphocytes, there are minimal data on ARV penetration in this organ. This study quantified total and protein-unbound splenic ARV concentrations, and determine whether drug transporters, sex, or infection status were modifiers of these concentrations in animal models and humans. Two humanized mice models [hu-HSC-Rag (n=36; 18 HIV+ and 18 HIV-); bone marrow-liver-thymus (n=13; 7 HIV+ and 6 HIV-)] and one nonhuman primate model [NHP; rhesus macaque (n=18; 10 SHIV+ and 8 SHIV-) were dosed to steady-state with ARV combinations. HIV+ human spleens (N=14) from National NeuroAIDS Tissue Consortium were analyzed post-mortem (up to 24h post-dose). ARV concentrations were measured by LC-MS/MS, drug transporter concentrations were measured with LC-MS proteomics, and protein binding in NHP spleens was determined by rapid equilibrium dialysis. Mice generally had the lowest splenic concentrations of the three species. Protein binding in splenic tissue was 6-96%, compared to 76-99% in blood plasma. NHPs had quantifiable Mrp4, Bcrp, and Ent1 concentrations, and humans had quantifiable ENT1 concentrations. None significantly correlated with tissue ARV concentrations. There was also no observable influence of infection status or sex. With these dosing strategies, NHP splenic penetration most closely resembled humans. These data can inform tissue pharmacokinetic scaling to humans to target HIV reservoirs by identifying important species related differences.
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