Initially, this year’s project was conceived as an upstream stage of drug-body interactions: drug-gene pharmacogenetic associations. However, as we continued research, our perspective broadened to how other antibiotics are required to manage chemotherapy-related symptoms. What if, we thought, we were able to extend antibiotic half-lives? Could this extended half-life remain effective while positively benefiting patients and tackling implementation issues like antibiotic resistance? These are the questions that drove our research this year.
Antibiotics have revolutionized modern medicine with their pivotal role in saving countless lives from bacterial infections. Additionally, antibiotic prophylaxis has become more common, with antibiotics given as a precaution to prevent infection before operations, reduce the risk of wound infections, and mitigate the negative effects of existing health complications [1].
Globally, antibiotic consumption was 40.2 billion defined daily doses (DDD) in 2018, an increase of 46% since 2000 [2]. Due to such a heavy reliance on antibiotics and suboptimal dosage, antibiotic resistance, the ability of the target bacteria to resist the effect of the antibiotic, has become a significant threat to the success of antibiotics. These resistant organisms are difficult to treat, requiring potentially toxic and expensive higher doses or alternative drugs [3]. According to the Center for Disease Control and Prevention (CDC), over two million people have become infected with antibiotic-resistant bacteria resulting in more than 23,000 annual deaths [4].
Global antibiotic stewardship programs have been enacted to ensure that the right drug, dose, and duration are selected when using a specific antibiotic. However, these programs also increase the complexity of outpatient procedures and place a larger burden on inpatient staff.
Improving antibiotics is one crucial focus area to fight antibiotic resistance and alleviate clinical burden. One such improvement is directly improving the pharmacokinetic properties of the drug by increasing the half-life of antibiotics, yielding friendlier dosing strategies and better management of infection.
While considering the applicability of improving the pharmacokinetic properties of different antibiotics, we took several major factors into consideration. These factors included antibiotic efficacy, clinical relevance, need for drug property improvement, healthcare infrastructure, and antibiotic resistance.
Carefully considering these reasons in collaboration with the wet lab team, we decided to focus our effort on cephalosporins. Cephalosporins are β-lactam antimicrobials used to treat infections caused by both gram-positive and gram-negative bacteria [5], lending to a wide breadth of efficacy, particularly in immunocompromised patients.
Agents in this class are prescribed for prophylaxis and empiric therapy. They are recommended as the first choice for preventing spontaneous bacterial peritonitis, biliary infections, infections from neurosurgery, and infections after urologic procedures. Additionally, healthcare providers use cephalosporins as alternative prophylactic antibiotics for neutropenic infections and infective endocarditis. Other empirical uses include treatment of central nervous system (CNS) infections like meningitis (since they can cross the blood-brain barrier), genitourinary tract infections, bone and joint infections, community-acquired pneumonia, and skin and soft tissue infections [6].
Although prescribed frequently in the United States and globally, cephalosporins are rapidly filtered by the kidneys, resulting in short half-lives ranging from 1 to 8 hours and the need for frequent dosing [7]-[9]. As a result, to ensure these drugs maintain efficacy without yielding antibiotic resistance, inpatient clinics are forced to provide rigorous dosing regimens several times daily for patients [10], increasing the burden on hospital staff.
In a study examining costs of four injected cephalosporins [11], the cost of the drug itself, the preparation and administration cost, and the consumable waste cost were compared. The latter two costs were higher for cefotaxime, ceftazidime and cefuroxime, which are normally administered three times a day, than for ceftriaxone, which is administered once daily. It was found that the percentage contribution of hidden costs to the healthcare system increased with decreasing antibiotic costs and were lower with higher dosage [11].
Similarly, for outpatient settings, complex regimens limit accessibility, are inconvenient, and add extra costs. With the difficulty in following these stringent guidelines, antibiotic resistance becomes commonplace, contributing to $3.4 billion in inappropriate ambulatory antibiotic usage [12]. By improving outpatient dosing scheduling, we aim to target more individuals who need treatment and reduce the risk of antibiotic resistance.
In summary, by manipulating the pharmacokinetics of cephalosporins, we aim to decrease the need for prolonged inpatient care and the difficulty in following complex dosing regimens for cephalosporins.
To read more about our solution, refer to our project description page.
By considering the different use cases of our albumin moiety linker and distribution strategies, we seek to ensure our approach’s technical feasibility and real-world applicability. Through collaborations with experts and stakeholders, we recognize the practical constraints, needs, and priorities crucial to emerging antibiotic technologies. Here, we aim to optimize the accessibility and efficacy of our technology, ensuring that our design has a tangible impact on the pressing challenges faced by healthcare providers and patients.
The core of our mission is to understand the needs and perspectives of those prescribing, administering, and receiving antibiotic treatment. By understanding clinician preferences and operational requirements, we can ensure that our technology is accessible to all members of the community and yield tangible results. We also aim to engage with patients’ perspectives as recipients of care.
We strongly emphasize the policies and regulations shaping the implementation and adoption of our solution. We recognize that requirements governing the development and deployment of new antibiotic technology are in place to minimize the effects of antibiotic resistance and ensure the safety of our community. Hence, by engaging with policy research and industry experts, we can develop an understanding of the regulatory framework and the best practices for enhancing the pharmacokinetic properties of existing antibiotics. Ultimately, by aligning our project with the ever-changing policy landscape, we can improve the likelihood of successful adoption and widespread impact.
The long-term impact of our solution is dependent on its adoption by the healthcare industry and success in meeting needs and expectations. By engaging with industry experts, healthcare providers, and potential users, we gain a comprehensive understanding of the current healthcare market and consumer needs. This knowledge allows us to strategically position our albumin-binding technology to address unmet needs and complement existing treatment options.
Due to the vast usage of antibiotics, our project could address many different issues. Based on our review of current literature and feedback from stakeholders, including physicians and clinical pharmacists, we have identified particular diseases and patient populations for which our half-life extension would be especially useful.
One potential application frequently brought up during research was outpatient antibiotic treatment. Multiple researchers, pharmacists, and physicians we spoke to, including Zahra Kassamali Escobar, Dr. Catherine Liu, and Dr. Kenneth Tham, noted that the current 8 hour dosing (q8h) of cephalosporins such as cefepime is difficult to administer in an outpatient setting and that there are currently no long-acting antipseudomonal antibiotics available.
Current efforts to mitigate issues with short intermittent dosing schedules focus on prolonging the infusion time of the antibiotic, keeping the blood concentration of the antibiotic above the minimum inhibitory concentration [13]. However, not all drugs are stable enough to be injected in an extended continuous manner.
As such, extending a cephalosporin’s half-life to allow for a q24h dosing regimen expands the antibiotic treatment options while also allowing patients to be discharged from the hospital earlier. Reduced hospitalization benefits both patients and hospital systems by allowing patients to return to their homes and by decreasing the strain on hospital resources.
In addition to outpatient treatment as a whole, we also identified specific conditions that would particularly benefit from this half-life extension, with Professor Brian Werth specifically mentioning sexually transmitted infections (STIs) such as gonorrhea and syphilis as a very relevant target. Professor Werth, an associate professor in the University of Washington School of Pharmacy, noted these diseases as especially relevant because cephalosporins are used to treat these illnesses [14], and these patient populations have a lower likelihood of consistently infusing. A longer-acting antibiotic would decrease the already significant burden on patients, and especially for very harmful diseases such as STIs, the benefits likely outweigh the potential risks.
To assess the overarching impacts of our project, we also analyzed existing health issues with third-generation cephalosporins and assessed whether our method would remediate or exacerbate these issues. Though antibiotics are used to treat many different illnesses, they can have harmful and unintended side effects; we believe that extending these antibiotics’ half-life would not worsen these problems and could possibly help address some of them.
One especially pressing health issue associated with cephalosporins that we identified early in our project development was seizures caused by drug neurotoxicity in patients with renal dysfunction. Patients with renal dysfunction often are unable to clear antibiotics from the body and accumulate a larger quantity of antibiotic, causing the antibiotic to cross the blood-brain barrier and leading to seizures [15]. While discussing this issue with Frank Tverdek, a clinical pharmacist at UW Medicine and Fred Hutch, he said he believed that our project could decrease the risk of neurotoxicity-based seizures in patients with renal dysfunction. Because our method leads to a slower release of the active form of the antibiotic, the peak concentration in the bloodstream is lower compared to the non-ABM conjugated form of the antibiotic, which would likely decrease the probability of the antibiotic entering the brain. Having passed these concerns to our modeling team, they confirmed this assumption- suggesting that blood concentrations would indeed not exceed the neurotoxicity threshold.
Frank Tverdek also informed us about allergic reactions to cephalosporins in some patients. He mentioned that one concern about dalbavancin, an extended half-life form of the gram-positive antibiotic vancomycin, was allergic reactions such as rashes increasing in severity due to the initial dose of antibiotic staying the body longer. Though this may still be a concern as our project also extends an antibiotic’s half-life, it is much less significant due to our extended half-life antibiotic only staying in the body in significant quantities for 24 hours (q24h), which is much less than the 2-week duration which currently available antibiotics such as dalbavancin last for [16]. Though allergic reactions are a potential problem that we will continue to evaluate, our current data shows that this should not be a significantly exacerbated concern.
Though neurotoxicity and allergic reactions are antibiotic-related health concerns that should not be discounted, arguably the most pressing unintended effect due to significant antibiotic use is antibiotic resistance. After discussing with multiple local individuals from a variety of backgrounds, we concluded that our project should not significantly increase existing concerns about antibiotic-resistant strains of bacteria. We learned from Frank Tverdek and Professor Brian Werth that the ideal conditions for antibiotic resistance development is a medium amount of antibiotic concentration for a long amount of time. Even though our project may seem to fit those criteria, Professor Werth noted (using similar reasoning as for our allergy concerns) that the relatively small magnitude of our extension would mean that the risk of antibiotic resistance development would not significantly increase, especially since other antibiotics stay in the body for that length of time [17]. Furthermore, Frank Tverdek added that this antibiotic resistance concern was an initial fear for dalbavancin that has not appeared significantly, indicating that our new drug likely will not face this issue. Antibiotic resistance is a pressing issue, but our project likely would not significantly exacerbate this problem.
For cephalosporins, neurotoxicity, allergic reactions, and antibiotic resistance are three major relevant problems. We wanted to ensure that our project did not worsen existing issues with these antibiotics. Though there are other unintended issues associated with antibiotics and cephalosporins in particular, our team has found that our project will not worsen and could even address three of these problems.
We spoke with Dr. Jennifer Huang, a hematology/oncology fellow at UW Medicine, to learn more about chemotherapy-induced neutropenia and receive feedback about how to increase the impact of our project.
We spoke with Dr. Ivan Huang, a Clinical oncology pharmacist at Fred Hutchinson Cancer Research who specializes in hematologic cancers, to expand our understanding of drug regimens, pharmacological decision making in patients with febrile neutropenia and where the best implementation strategies for our project life.
We spoke with Dr. Kenneth Tham, a Clinical oncology pharmacist at Fred Hutchinson Cancer Research who specializes in thoracic, head and neck, and gastrointestinal cancers.
We spoke with Dr. Catherine Liu, the director of Antimicrobial Stewardship and Outpatient Parenteral Antimicrobial Therapy Programs at Fred Hutch, to learn more about the impact of our project in the context of patient treatment and antibiotic resistance.
We met with Dr. Frank Tverdek, a clinical pharmacist focusing on infectious diseases and antimicrobial stewardship, to hear about how our project could be integrated clinically.
We met with Dr. Zahra Kassamali Escobar, who works on infectious disease treatment in the outpatient space, to hear additional thoughts about how to effectively implement our project.
We spoke with Professor Brian Werth in the UW Department of Pharmacy to hear his feedback on our project based on his strong background with long half-life antibiotics, particularly dalbavancin, an extended half-life form of vancomycin.
We spoke with Dr. Jesse Fann, the medical director of Fred Hutchinson’s department of Psychosocial oncology to hear about how our project will affect the mental health related challenges faced by oncology patients.
We interviewed Dr. Cutter to learn how our protein-linker design would affect healthcare workers.
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Fast facts [18]:
Cefepime is often given as a first-line antibiotic for febrile neutropenia, as Dr. Ivan Huang explained to us. Dr. Catherine Liu added further information about its use as a general antibiotic in cases of serious infection because of its broad spectrum of activity and ability to target Pseudomonas aeruginosa. This sets it apart from other broad-spectrum antibiotics like ertapenem. Unfortunately, while ertapenem is injected once a day, cefepime requires a dosing schedule of every 8 hours (or even 6 hours in patients with kidney impairment) [19].
It is also not universally able to be given in a continuous infusion. Although it is stable for around 24 hours at 25 degrees C, it is stable for only 13 hours at 37 degrees C, meaning a continuous infusion would be unsuccessful if stored near the body or administered in warm environmental conditions [20].
If our project could extend this dosing schedule to every 24 hours, Dr. Huang said it could significantly cut inpatient nursing time. Dr. Kenneth Tham and Dr. Catherine Liu were both excited by our project’s value in the outpatient setting. Needing a cefepime infusion only once a day (as opposed to three or four times a day) makes outpatient treatment more accessible to patients, limiting the need for inpatient hospitalization and improving patient outcomes for gram-negative infections that need long-term treatment (7-14 days). With this knowledge, we proceeded to use cefepime as our headlining example.
Fast facts [21]:
Cefotaxime was considered as a potential use case for our system because of its q8h dosing. In our conversations with Frank Tverdek and Zahra Kassamali-Escobar, we learned that there is a clinical shortage of cefotaxime in the United States due to manufacturer discontinuation [23]. Additionally, ceftriaxone, a third-generation cephalosporin often used interchangeably with cefotaxime, has a more ideal dosing schedule of q12h or q24h [24], [25]. However, ceftriaxone is not perfect, as recent research in neonatal patients shows ceftriaxone increases the risk of biliary pseudolithiasis and calcium chelation. Researchers are now recommending the use of cefepime and ceftazidime as alternatives in higher-risk patients [26].
Additional research has shown neonates given ceftazidime have significantly higher rates of necrotizing enterocolitis, a highly fatal intestinal disease, than those given cefotaxime [27]. These complications indicate that our project can reduce the strain on care providers for administering doses of cefotaxime while potentially keeping vulnerable neonatal patients safer.
Fast Facts [5], [28]:
Cefazolin is an antibiotic brought to our attention by Zahra Kassamali-Escobar and Professor Brian Werth as an additional use case for our ABM system. When treating gram-positive infections or other moderate to severe infections, it must be dosed every 6 to 8 hours [29], [30].
To reduce dosing frequency, cefazolin can be administered in a prolonged infusion ranging from 3 hours to longer than 24 hours [31] - [33]. While this is effective in raising the concentration of the drug above the MIC for a longer period (increasing the efficacy of the drug) [34], it also means that the patient must deal with storing the drug carefully to avoid degradation and managing some sort of constant-infusion pump or elastomeric balloon pump system for the duration of treatment - which for osteomyelitis is a median of 6 weeks! Our system would similarly raise the concentration of the drug while taking only around 30 minutes per injection, improving patients’ quality of life. We have passed this information on to our modeling teams to learn the required cefazolin dosing specifics for a q24h or q12h extension time.
As a team, we designed our albumin binders around intravenous (IV) antibiotic delivery. IVs have two main use settings: inpatient and outpatient. The team entered the project thinking we could improve both inpatient and outpatient treatment. However to determine if this was possible, we needed to talk to people actually involved in that process. We spoke to Dr Erin Cutter, a clinical pharmacist who walked us through how IVs are prepared at a hospital.
Dr. Cutter showing us the cefepime bottle used in IV prep
For a simple preparation process, lyophilized antibiotic is suspended via a needle injection with a solution of saline or 5% dextrose. This is then added to the IV bag, which gets sent to the nurse and is delivered to the patient. Dr. Cutter estimated that this preparatory process for the pharmacist takes about 2 minutes.
One problem our team has experienced in the design process has been the challenge of connecting the antibiotic and the linker along with the protein. The linker-antibiotic connection requires a lower pH to facilitate binding. Dr. Cutter explained that in similar situations, pharmacists use diluent solutions to adjust conditions before reverting the solution back to blood pH (before delivery into the body). She did tell us that, ideally, preparation would only require 1 or 2 steps of solution treatment. Based on further literature research, we found that HCl and NaOH are two common chemicals used to adjust the pH of solution back to that of blood after reaction step completion.
Dr. Cutter noted that many antibiotic IV treatments operate on scheduled cycles, so if a final protocol required wait times, this likely would not pose a significant problem. We also learned that storage of the protein and linkers would not pose capacity challenges to the average United States clinical pharmacy, which can maintain both at the proper temperatures. From this input, we believe that our design could be integrated into the existing clinical pharmacy system for preparing IVs.
We reached out to Dr. Jesse Fann (medical director of psychosocial oncology at Fred Hutch) to discuss the psychological impact our project may have. He explained that our project’s largest impact would be the ability to increase at-home care as opposed to inpatient care. This is such a big deal, he said, because good at-home care leads to lowered depression, anxiety, and delirium rates which are, unfortunately, extremely common issues seen in oncology patients. Being at home also tends to lift patient’s spirits as well which in turn can lead to better physical and mental health outcomes [35].
Dr. Erin Cutter (clinical pharmacist) detailed several benefits we had not considered that are particularly relevant to our home city of Seattle. Our city has a large unhoused population as well as a significant population of IV drug users. For both groups, IV antibiotic treatment can be difficult. Outpatient self-administered treatment necessitates the use of a central line port. However, this is not an option for the unhoused or IV drug users. Central lines are prone to infection and so must be kept extremely clean. Additionally, they pose a risk by facilitating IV drug use. In the case of either population, hospitals must hospitalize them, which is extremely expensive for the hospital (as neither population is likely able to pay the cost). The United States Center for Disease Control puts the average cost for a day of hospitalization at around $14,000 [36]. However, by decreasing dosage frequency from three to one time per day, our system creates a new option for patient treatment. Instead of being hospitalized or having a central venous catheter (CVC) installed, they can visit daily to receive their IV treatment. While still inconvenient for patient time, this is significantly more cost-effective than hospitalization when dealing with the unhoused and IV drug-using population.
The process of drug lifetime extension may also benefit other patient groups that otherwise could get outpatient treatment through a central line. Outpatient central lines also have a high rate of complication (approximately 20%)- primarily from infection along the line itself [37]. Treatment via central line also poses a not insignificant cost; one estimate puts the individual price of a central catheter as around $300 [38]. A daily in-person treatment option would allow the patient the option of simply visiting a clinic each day instead of needing to get and maintain a central line.
Dr. Cutter noted the benefits of dosage extension would also carry to the hospitalized patients. Only applying treatment once a day would reduce disturbance of the IV line- reducing the risk of infection. While we can't precisely estimate how long it would take to prepare an IV with our design, we do know that reducing the frequency of dosing reduces the workload for nurses. We also probably keep steady or do not significantly increase the workload for clinical pharmacists since they now only need to prepare one IV for the patient instead of three each day (in the case of cephalosporins like cefepime). Even if the individual IV prep process becomes more involved due to the multiple steps of the linker, the pharmacist will only have to do it once.
In short we found that our proposed system could both improve patient outcomes and save money for the healthcare system overall.
We know that our Albumaxing moiety system does not exist in a vacuum, so we conducted research to determine market-shaping and regulatory factors that would affect the implementation of our project from the lab space into real-world healthcare systems.
The global market for antibiotics is estimated at $48-50 billion with a compound annual growth rate of 4.1-4.2% [39], [40]. The North American region is responsible for around 25-30% of the global market, with the United States accounting for around half of that number (12% of the total market) [41], [42]. Using these figures, we can estimate the size of the United States antibiotic market to be around $5-6 billion.
More specifically, our project’s initial development focuses on cephalosporins. Cephalosporins form a large segment of the total antibiotic market because of their generally broad spectrums of coverage. The global market size for cephalosporins is estimated to be $17-19 billion. The cephalosporin market is also expected to grow at the fastest rate per year among all antibiotic class segments [7], [43], [44]. In the United States, cephalosporins have been the most commonly prescribed antibiotic class, accounting for nearly 31% of all prescribed antibiotic injections [45]. While our extension system is not the best option for every cephalosporin, the approximately $2 billion United States cephalosporin market is a valuable initial target market.
Other firms have worked on peptide-drug conjugates (PDCs), which take advantage of the cell-targeting abilities of specific peptides to deliver payloads. PDCs bind to smaller homing peptides and can more easily access tumor tissue, making them a promising area of research for oncology care [46]. Similarly, Antibody-Drug conjugates (ADCs) use antibodies to improve the targeting specificity of the partnered therapeutic [47]. Examples of products utilizing this technology are Mylotarg (Gemtuzumab ozogamicin) and Besponsa (Inotuzumab ozogamicin) [48], which conjugate the drug calicheamicin with antibodies targeting specific proteins in cells with leukemia. Ongoing research is also being conducted to increase the efficacy of antibiotics like vancomycin [47]. There are currently 11 ADCs in the market and many times more in development [49].
However, one limiting factor in PDC development is the short half-life and rapid clearance of the therapeutics from the body [50]. Because of albumin’s neonatal Fc receptor-mediated recycling, albumin-conjugated proteins have extended half-lives, making albumin fusion either via linkers or directly adding albumin domains to peptide therapeutics a promising area of research [46], [51].
Namely, firms like ConjuChem have designed ways to conjugate to albumin either pre- or post-injection (the Drug Affinity Complex and Preformed Conjugate-Drug Affinity Complex, respectively) to extend or modify the half-life of drugs treating diabetes and HIV [52], [53]. Their CJC-1134-PC product conjugates Exendin-4 (a diabetes treatment) to albumin and increases its half-life significantly from less than 1 hour to multiple days [53], [54]. This product is now in phase III trials [54]. Another use of reversible albumin binding is Victoza (liraglutide), which uses a fatty acid to bind to albumin, resulting in protection and a slower release of the GLP-1 analog to treat diabetes [55], [56].
While these existing products are conceptually similar, our MightyMoiety system is, to our knowledge, a novel method of extending antibiotic half-life with much potential for growth in an emerging market.
Although our final product will be sold as part of specific antibiotics to healthcare systems, a feasible goal for our team is to develop the technology as much as possible while targeting large pharmaceutical companies currently distributing cephalosporin antibiotics. Large firms like Pfizer, which own Maxipime (branded cefepime) and produce generic cefazolin, have resources necessary to take our idea to market and would benefit from our product making these cephalosporins more appealing options for prescription.
While creating a cephalosporin conjugation/half-life extension system, we must consider the appropriate use of antibiotics in order to deal with issues such as antibiotic resistance and patient safety.
The United States Food and Drug Administration (FDA) begins by recommending antibiotic use only for treating confirmed infections. As such, our product should also be used only in patients with confirmed bacterial infections.
FDA guidelines also indicate the implementation should be specific to the target cephalosporin. Damaging the structure of the drug or non-specifically binding to different molecules in the body could decrease drug effectiveness and be a concern to patient safety.
Successfully confirming the above two through a variety of tests necessitates the implementation of comprehensive antimicrobial stewardship programs, including drug use education, monitoring of patients who received the drug, and improving existing processes of distribution and application.
Lastly, the dosage should be administered in the shortest possible duration to mitigate resistance while optimizing the effectiveness of the drug. As this concerns patient safety, it is necessary to determine any effect of the linker beyond half-life and adapt the existing dosage to an appropriate level. Keeping these in mind, we researched a brief product strategy integrating policy and regulatory requirements.
This initial phase will focus on considerations for our conjugate using regulations for antibody-drug conjugates (ADC) as a launchpad. With our primary goal to extend the half-life of our drug, selection of the optimal dosing strategy is extremely important. Though specifics will vary for each drug, our system was designed for less frequent IV dosing every 12 or 24 hours. The FDA recommends assessing a broad dose range early during drug development to inform dose selection of the ADC [57].
Bioanalytical testing conducted during this phase will adhere to the FDA’s released guidance for industry method validation. Examples of parameters include the small molecule type, the molecular formula, the biological matrix, and the calibration range in the analyte measured [58].
Additionally, this phase is when our team would continue refining the connection and conjugation process before entering preclinical testing.
The primary objectives of preclinical testing include assessing safety and evaluating efficacy in in vitro and relevant animal models. In practice, we would use toxicology studies to determine safety and the pharmacokinetics/pharmacodynamics (PK/PD) of how the moiety behaves in biological systems, particularly its absorption, distribution, metabolism, and excretion (ADME) and binding affinity to albumin [59].
We will conduct in vitro assessments of drug-drug interaction risks associated with drug-metabolizing enzymes and transporters for both the unconjugated payload and our albumin-binding moiety. Should the in vitro studies not indicate potential risks, we are prepared to conduct in vivo studies as the FDA recommends [57]. We recognize that even a small increase in systemic exposure of the cytotoxic payload can significantly impact safety, and we will take appropriate measures to assess this risk thoroughly.
Stability testing will include more robust studies encompassing both acute and chronic toxicity assessments along with evaluations for carcinogenicity and reproductive toxicity [60]. Formulation development is also crucial to ensure the compound remains consistent and safe over time, as well as compatibility assessments to cephalosporins. Due to physical administration and IV solution, the conjugate should be prepared for different environments [60].
Another important consideration is the dose-to-exposure response. As we need to fully understand the reaction of individuals to the moiety, testing the effect of the moiety on albumin and on how long the binder circulates is essential to minimizing hazardous risks to the individual [61]. Critically, intrinsic factors may affect the exposure of our albumin-binding moiety. We plan to conduct population pharmacokinetic (PK) analyses and dedicated studies to assess the impact of factors such as organ impairment or existing health conditions [62]. This evaluation will inform our labeling strategy and dosing recommendations, especially to identify any populations for which dosing should be avoided.
The QT interval also occupies a pivotal role in drug development for animal studies [63]. Since the prolongation or shortening of the QT interval may yield serious cardiac arrhythmias, we will ensure that our assessment includes evaluating the unconjugated payload, linker, and any relevant metabolites for potential QT prolongation. This approach aligns with established principles for small-molecule drugs and will help us identify any associated risks.
Additionally, we plan to evaluate the potential for immunogenicity as mentioned above. This includes safe testing in animal models to assess immune responses and clear documentation and reporting of all preclinical studies, ensuring that methodologies, results, and any deviations are meticulously recorded [64]. Lastly, seeking input from institutional review boards (IRBs) or ethics committees further ensures compliance with ethical standards throughout the development process [65].
This clearly documented data will be used in the Investigational New Drug (IND) application to demonstrate safety and justify human trials [64]. The IND application is required by the U.S. Food and Drug Administration (FDA) before any clinical trials can begin involving human subjects [66]. This regulatory requirement is in place to safeguard participants by ensuring that the proposed studies are grounded in sufficient preclinical evaluation.
The IND application includes a comprehensive overview of the moiety and preclinical data. The clinical protocols section is a cornerstone of the IND application, as it outlines the design and methodology of the planned clinical trials. Additionally, manufacturing information, safety monitoring, and statistical analysis plans should outline comprehensive plans for participant safety oversight. A well-defined statistical approach is essential to provide scientifically valid and interpretable trial results [66].
Lastly, the IND application must address regulatory and ethical considerations. Confirming that the study will be reviewed and approved by an Institutional Review Board (IRB) is vital to protect participant rights and welfare. Furthermore, outlining the process for obtaining informed consent ensures that participants are fully aware of potential risks and benefits associated with the study [64]-[66].
The next phase will move us into clinical research. Phase I trials will include about 20-80 people and aim to confirm dosage and safety in human subjects. PK/PD analysis will be used in this phase. Phase II trials will include several hundred patients and provide us with efficacy data and more safety information. The next stage, Phase III, will include monitoring thousands of patients for side effects and potential drug-drug interactions [64], [67]. It is in this phase that optimal dosing strategies will be finalized. With completed clinical trials and dosing information, it will be possible to analyze the market to determine a starting price point for market adoption.
Before our product can enter the market, we must submit a New Drug Application to the FDA with all clinical data, compliance information, and safety information [68]. If approved, the product will enter the market with continued monitoring and surveillance in the market to ensure safety [69].
Due to the high expenses of conducting clinical trials, it seems the best chance to ensure our product completes the trial process is to use successful preclinical or phase I data to search for investors and venture capital funding. An alternative is to be acquired by a company like Pfizer, which will have the resources to complete research.
Previous sections of this page describe how the Human Practices team has worked with our other subteams to discover issues with current cephalosporin delivery and ideate an albumin-binding moiety solution. This system has value for healthcare providers who not only have reduced burden of IV preparation but also can use certain cephalosporins (especially those too unstable to be given in a prolonged infusion) for longer periods without creating more antibiotic resistance. Our Albumaxing moiety also helps patients by reducing dosing frequency (potentially reducing adverse drug responses) and psychologically by reducing the necessity of inpatient hospital care and time spent with infusion apparatuses.
Excitingly, since our conjugation system utilizes the carboxylic acid group found on cephalosporins, we believe our project could also be used to increase the half-lives of other commonly prescribed beta-lactam antibiotic classes like penicillins and carbapenems. Future research has much potential to enhance the use of existing and newly-developing antibiotics.
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