Therapeutic Exposure Research Articles

541 Effect of therapeutic antibiotic exposure on oropharyngeal and fecal microbiota in infants with cystic fibrosis

541 Effect of therapeutic antibiotic exposure on oropharyngeal and fecal microbiota in infants with cystic fibrosis

Prevalence of Solitary Thyroid Nodule in Patients Admitted in Hospital of Dera Ismail Khan, KPK, Pakistan

Solitary nodules are a typical thyroid disease appearance. Solitary thyroid nodules are little swellings that are ordinarily impalpable glands. Solitary thyroid nodules are typically benign. With a mean age of 35 years, ladies are more likely than males to develop cancer (10–20%). An endocrine gland called the thyroid is located in the lower front and sides of the neck. Its primary purpose is to regulate basal metabolic rate. It also promotes somatic and psychic growth and is crucial for calcium metabolism. The identification, examination, and treatment of thyroid nodules can be difficult. These lumps frequently develop near the thyroid gland's border and are enormous in size, causing them to feel or seem like a lump in front of the neck. A multitude of variables, including age, sex, food, iodine deficiency, and even therapeutic and ambient radiation exposure, affect the occurrence of these nodules in a given population. This study was conducted in hospital of Dera Ismail Khan, KPK,Pakistan to determine the prevalence of solitary thyroid nodules in patinets admitted in the hospital. The results indicates that females between the ages of 26 and 30 are more likely to have thyroid nodules. Swelling at the front of the lower neck is the most frequent presenting ailment. The majority of patients presented between 6 months and 3 years after the edoema first appeared. The sensitivity and specificity of FNAC in the current investigation were 92% and 98%, respectively, while sensitivity and specificity of USG were 70 and 90%, respectively. Histopathology verified all malignant tumours on FNAC, demonstrating its superiority. USG and FNAC aids in proper management planning as a result, preventing the need for additional surgery. Keywords: Solitary thyroid nodule; Thyroid neoplasm; Neck swelling; Body mass index; Pakistan

Investigation of Alogliptin-Loaded In Situ Gel Implants by 23 Factorial Design with Glycemic Assessment in Rats.

The aim of the study was to design injectable long-acting poly (lactide-co-glycolide) (PLGA)-based in situ gel implants (ISGI) loaded with the anti-diabetic alogliptin. Providing sustained therapeutic exposures and improving the pharmacological responses of alogliptin were targeted for achieving reduced dosing frequency and enhanced treatment outputs. In the preliminary study, physicochemical characteristics of different solvents utilized in ISGI preparation were studied to select a proper solvent possessing satisfactory solubilization capacity, viscosity, water miscibility, and affinity to PLGA. Further, an optimization technique using a 23 factorial design was followed. The blood glucose levels of diabetic rats after a single injection with the optimized formulation were compared with those who received daily oral alogliptin. N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), as highly water-miscible and low viscous solvents, demonstrated their effectiveness in successful ISGI preparation and controlling the burst alogliptin release. The impact of increasing lactide concentration and PLGA amount on reducing the burst and cumulative alogliptin release was represented. The optimized formulation comprising 312.5 mg of PLGA (65:35) and DMSO manifested a remarkable decrease in the rats’ blood glucose levels throughout the study period in comparison to that of oral alogliptin solution. Meanwhile, long-acting alogliptin-loaded ISGI systems demonstrated their feasibility for treating type 2 diabetes with frequent dosage reduction and patient compliance enhancement.

P2.16: Influence of Immunosuppressive Drugs on NK Cells in Therapeutic Drug Exposure

P2.16: Influence of Immunosuppressive Drugs on NK Cells in Therapeutic Drug Exposure

P21-11 Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach

Different government agencies operating in the European Union regulate different types of chemical products but all require testing for carcinogenicity to support applications for product marketing and commercialisation. A conference was held in Brussels in 2013 where representatives of the pharmaceutical, animal health, chemical and plant protection industries, together with representatives of regulatory agencies, universities and other stakeholders, met under the auspices of The European Partnership for Alternative Approaches to Animal Testing (EPAA) to discuss the varying requirements for carcinogenicity testing, and how these studies might be refined to improve hazard evaluation and risk assessment while implementing principles of the 3Rs (replacement, refinement and reduction in animal studies). While there are some similarities, the regulatory approaches in pharmaceutical, animal health, chemical and plant protection sectors have varying degrees of flexibility in requirements for carcinogenicity testing, to an extent reflecting concerns over the magnitude and duration of human exposure, either directly as in therapeutic exposure to pharmaceuticals, or indirectly through the ingestion of residues of veterinary drugs or plant protection chemicals. The article discusses these differences and other considerations for modified carcinogenicity testing paradigms on the basis of scientific and 3Rs approaches.

Syncarcinogenesis of natural UV radiation and polycyclic aromatic hydrocarbons in the development of squamous cell carcinomas of the skin?

Squamous cell carcinomas (SCC) of the skin can be induced by occupational exposures to polycyclic aromatic hydrocarbons (PAHs), as in tar and soot, or to UV radiation and can be recognized and compensated as occupational diseases. A possible syncarcinogenic effect of these exposures in the development of SCC in humans is under discussion. For the scientific validation of this question, a systematic literature search was conducted using the databases PubMed, Web of Science, and Scopus. Studies on individuals with SCC of the skin and their precursors as well as occupational, non-occupational, or therapeutic exposure to UV radiation and PAHs were selected. In addition, animal studies with exposure to UV radiation and PAHs were evaluated. After screening the abstracts of 510 identified studies, the full texts of 131 studies were reviewed. None of the epidemiological studies provided robust evidence for a syncarcinogenesis of PAHs and UV radiation in the development of SCC of the skin in humans. Nevertheless, as there are indications for a (super-)additive effect of UV radiation and PAH exposure from animal studies and mechanistic investigations, syncarcinogenesis seems possible. However, quantitative dose-response relationships are lacking which would allow comparison of the onset of an adverse effect between the different exposure levels.

Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.

Population pharmacokinetics and clinical outcomes of polymyxin B in paediatric patients with multidrug-resistant Gram-negative bacterial infections.

Current polymyxin B dosing in children relies on scant data. To build a population pharmacokinetic (PK) model for polymyxin B in paediatric patients and assess the likely appropriateness of different dosages. A total of 19 paediatric patients were enrolled to receive intravenous polymyxin B (1.33-2.53 mg/kg/day), and the median age was 12.5 (range 3.2-17.8) years. Serial plasma samples were collected at steady-state and modelled by population PK analysis. Clinical efficacy and nephrotoxicity of polymyxin B treatment were also assessed. PK data were adequately described by a two-compartment model with first-order elimination, and weight was a significant covariate of polymyxin B clearance. Clinical success occurred in 14 of 19 patients (73.7%) and only one patient developed acute kidney injury. The 28 day mortality was 10.5% (2/19). The steady-state polymyxin B exposure was 36.97 ± 9.84 mg·h/L, lower than the therapeutic exposure of 50-100 mg·h/L. With the AUC24h/MIC target of 50, the dosage of 1.5-3.0 mg/kg/day had a probability of target attainments over 90% when MICs were <0.5 mg/L. Dose adjustment of polymyxin B needs to consider the MIC of infecting pathogens. Current polymyxin B dosing for paediatric patients may be acceptable when MICs are <0.5 mg/L.

Assessment of the Carcinogenic Potential of Pretomanid in Transgenic Tg.rasH2 Mice.

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved as part of a three-drug oral regimen, consisting of bedaquiline, pretomanid, and linezolid, for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis or with complicated forms of multidrug-resistant tuberculosis by the food and drug administration in the United States and regulatory bodies in over 10 other countries. Nitroaromatic compounds as a class carry a risk of genotoxicity and potential carcinogenicity based on reactive metabolite formation. A battery of good laboratory practice genotoxicity studies on pretomanid indicated that the compound was not genotoxic, however its hydroxy imidazole metabolite (M50) was genotoxic in the Ames assay. To assess the in vivo carcinogenic potential of pretomanid, hemizygous Tg.rasH2 mice were administered pretomanid once daily by oral gavage for 26 weeks. Male mice were given pretomanid in vehicle at doses of 0, 5, 15 and 40 mg/kg/day and female mice were given pretomanid in vehicle at doses of 0, 10, 30 and 80 mg/kg/day. Positive control mice of both sexes received intraperitoneal injections of urethane at 1000 mg/kg on Days 1, 3 and 5. There were no pretomanid-related early deaths, tumors, non-neoplastic microscopic findings, or gross necropsy findings at any dose level. The positive control gave the anticipated response of lung tumors. Oral administration of pretomanid to mice produced plasma exposure to the parent compound (high dose AUC of pretomanid 3 times the clinical AUC at the maximum recommended human dose) and exposure to the M50 metabolite (less than 10% of pretomanid) at all dose levels in both sexes. These data show that pretomanid was not carcinogenic in a transgenic mouse model at systemic exposures greater than human therapeutic exposures.

Systematic Comparison of Hospital-Wide Standard and Model-Based Therapeutic Drug Monitoring of Vancomycin in Adults.

We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or continuous vancomycin infusions. Each patient provided two randomly selected pairs of two consecutive vancomycin concentrations. A web-based precision dosing software, TDMx, was used to evaluate the model-based approaches. In total, 154 patients contributed 308 pairs. With standard TDM-based dosing, only 48.1% (148/308) of all of the second concentrations were within the therapeutic range. Across the model-based approaches we investigated, the mean relative bias and relative root mean square error varied from −5.36% to 3.18% and from 24.8% to 28.1%, respectively. The model averaging approach according to the squared prediction errors showed an acceptable bias and was the most precise. According to this approach, the median (interquartile range) differences between the model-predicted and prescribed doses, expressed as mg every 12 h, were 113 [−69; 427] mg, −70 [−208; 120], mg and 40 [−84; 197] mg in the case of subtherapeutic, supratherapeutic, and therapeutic exposure at the second concentration, respectively. These dose differences, along with poor target attainment, suggest a large window of opportunity for the model-based TDM compared with the standard TDM-based vancomycin dosing. Implementation studies of model-based TDM in routine care are warranted.

Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically-based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (AUC0-inf and Cmax), following oral administration were within 2-fold of observed values for the dog and monkey, and close to 2-fold for the rat, providing validation to the model structure. Adaptation of this oral PBPK model to humans, using human physiological parameters coupled with predicted human PK, resulted in underpredictions of vismodegib exposure following both single and multiple doses. When observed human PK was used to drive the oral PBPK model, oral PK profiles in humans were well predicted with fold errors in predicted vs observed drug exposures being close to 1. Importantly, the oral PBPK model captured the unique nonlinear, non-dose dependent PK of vismodegib at steady-state. The mechanism responsible for nonlinearity was consistent with oral absorption being influenced by nonsink permeation conditions. We introduce a new parameter, the permeation gradient factor, to characterize the effect of nonsink conditions on permeation. Using vismodegib as an example, we demonstrate the value of using oral PBPK models in drug discovery to predict the oral PK of compounds with nonlinear absorption characteristics in human. Significance Statement A physiologically-based pharmacokinetic model was built to demonstrate the value of these models early in the drug discovery stage for the prediction of human PK for compounds with unusual oral pharmacokinetics. In this study, our model could successfully capture the unique steady-state oral pharmacokinetics of our model compound, vismodegib. The mechanism for nonlinearity can be attributed to nonsink permeation conditions in vivo. We introduce the permeation gradient factor as a parameter to assess this effect.

Joint Disposition Properties and Comprehensive Pharmacokinetic Characterization of Antibody–Drug Conjugates

Antibody–drug conjugates (ADCs) comprise 3 distinct parts: a specific antibody carrier (mAb), a linker, and a cytotoxic payload. Typical pharmacokinetic (PK) characterization of ADCs remains fragmented using separate noncompartmental analyses (NCA) of individual analytes, offering little insight into the dynamic relationships among the ADC components, and the safety and efficacy implications. As a result, it is exceedingly difficult to compare ADCs in terms of favorable PK characteristics. Therefore, there is a need for characterizing ADCs using the joint disposition properties critical for understanding the fate of an ADC complex and clinical implications. In this communication, we describe 3 joint disposition metrics (JDMs) for integrated NCA of ADCs based on a combination of common analytes of ADC, payload, conjugated payload, and total mAb. These JDMs were derived, each in a simple form of a ratio between appropriate PK parameters of two analytes, from the presumed drug delivery scheme behind typical ADC designs, in terms of (1) linker stability, (2) therapeutic exposure ratio, and (3) effective drug-to-antibody ratio in vivo. The validity of the JDM-based PK characterization was examined against model-based analyses via their applications to 3 clinical candidates: PF-06650808, PF-06647020, and PF-06664178. For instance, the linker stability estimates for PF-06650808, PF-06647020, and PF-06664178 were 0.31, 0.14, and 0.096, respectively, from the JDM-based analyses vs. 0.23, 0.11, and 0.086 by the model-based approach. Additionally, the JDMs were estimated for a number of FDA-approved or otherwise well-documented ADCs, showing their utilities in comparing ADCs in terms of favorable PK characteristics.Graphical

Calibration and validation of the rabbit model of electrolytic-mediated arterial thrombosis against the standard-of-care anticoagulant apixaban.

Apixaban is a factor Xa (FXa) inhibitor and standard‐of‐care anticoagulant with FXa Ki and plasma protein binding (free fraction) averages 0.08 nM and 0.13 in humans and 0.16 nM and 0.37 in rabbits, respectively. Apixaban at the approved dose of 5 mg BID achieved maximum and minimum plasma concentration of 373 nM (95% CI: 198 – 699 nM) and 224 nM (95% CI 89–501 nM), respectively, in patients with nonvalvular atrial fibrillation (AF). We calibrated the rabbit model of electrolytic‐mediated arterial thrombosis (ECAT) against apixaban and correlated the potencies derived from the rabbit ECAT to in vivo efficacious exposure levels in AF patients. Vehicle and apixaban at multiple doses were infused IV in ECAT rabbits and their effects on thrombus weight were measured. Apixaban exhibited dose‐related efficacy in preventing thrombosis in ECAT rabbits with EC20, EC50, EC60, EC70 and EC80 of 18, 101, 169, 296, and 585 nM, respectively. After correcting for the human‐to‐rabbit potency based on FXa Ki and plasma protein binding, we estimated a rabbit‐equally‐effective plasma concentration of 157 and 259 nM to the trough and peak plasma concentration in AF patients treated with 5 mg BID of apixaban. These rabbit‐equally‐effective plasma concentrations matched well with the rabbit ECAT EC60 and EC70. This study supports the potential of the rabbit ECAT to predict in vivo therapeutic drug exposure of FXa inhibitors. Achieving human‐equally‐effective plasma concentrations to the rabbit ECAT EC60 and EC70 may produce clinical efficacy in patient populations like AF.

Antibody-drug conjugate (ADC) joint disposition properties and their clinical utilities for comparative assessments in terms of favorable pharmacokinetic (PK) characteristics.

e15005 Background: PK characterization of ADCs is often fragmented using separate analyses of individual analytes. As such it is difficult to compare among ADCs in terms of PK characteristics critical for understanding the fate of an ADC complex as a whole and its clinical implications. While several integrated PK models have been applied to clinical datasets, these have been mostly for the purpose of identifying covariate effects on PK parameters. In this abstract, we propose 3 joint disposition metrics for integrated PK characterization of ADCs based on a combination of concentrations of ADC, payload (PL), conjugated payload (CPL), and total mAb (TAb, ADC plus unconjugated mAb) in the blood, and for defining what are favorable PK characteristics for ADCs. Methods: The joint disposition metrics representing linker stability (AUCmAb/AUCTab), therapeutic exposure ratio (CLPL/CLADC) and effective drug-antibody ratio (DAR) (AUCCPL/AUCADC), were derived mathematically from a framework of typical ADC designs and verified via modeling approaches using PK data of 3 clinical candidates, an anti-Trop2 ADC (PF-06664178) [King GT, et al. Invest New Drugs 2018;36(5):836-847], an anti-Notch3 ADC (PF-06650808) [Rosen LS, et al. Invest New Drugs 2020;38(1):120-130], and an anti-PTK7 ADC (PF-06647020) [Maitland ML, et al. Clin Cancer Res 2021;27(16):4511-4520]. Furthermore, the joint disposition metrics were calculated for a number of FDA-approved or otherwise well documented ADCs, which were selected as the information on ADC, payload and TAb analytes is available, to examine their clinical utilities in assessing among ADCs in terms of favorable PK characteristics. Results: The validity of the joint disposition metrics was demonstrated and verified for integrated PK characterization of ADCs. Estimates of the joint disposition metrics, for the linker stability, therapeutic exposure ratio and effective DAR, were obtained for the selected ADCs products and candidates (Table below), consistent with the expectation based on clinical experience. Conclusions: Three joint disposition metrics were derived for integrated PK characterization of ADCs using conventional PK analytes. Their clinical utilities were explored in assessing among ADCs in terms of favorable PK characteristics. Analyses of additional ADCs may be needed to further validate these metrics for broader usage.[Table: see text]

Optimal timing and interval of imaging for metastatic breast cancer.

1106 Background: Breast cancer is a family of diseases with varying disease trajectories based on intrinsic biology of the tumor. The time of progression varies across & within subtypes, and with increasing rates of drug resistance depending on prior therapeutic exposure. There is no strong consensus about optimal surveillance and routine imaging in patients with metastatic breast cancer (mBC), but many oncologists report that monitoring strategies are based on strategies used in clinical trials. Methods: We reviewed 17 prior Phase III studies that led to FDA approval in mBC. We reviewed 8 studies for ER+ mBC, 5 studies for HER2+ mBC, 2 studies for triple negative (TNBC) mBC, and 2 studies for BRCA+ mBC. We calculated rates of progression or death (POD) per month for the first year on therapy using data from survival analysis tables and compared them across the different types and lines of therapy. Results: Risk of progression in mBC varies based on receptor status and line of therapy (Table). There was a significant difference in POD rates between ER+ therapies compared with all other disease types (HER2+, TNBC, BRCA) (p = 0.012). Patients with TNBC or receiving PARP inhibitors or later line HER2 therapies had higher POD rates than those with ER+ breast cancer or receiving first line HER2 therapy (6.9% vs 4.1% per month; p = 0.0004). No significant difference was seen in the monitoring frequency between ER+ and HER2+ disease (p = 0.39). Conclusions: These data suggest that shorter interval imaging should be performed for patients with TNBC or receiving PARP inhibitors or later line HER2 therapies. Surveillance imaging for patients with mBC should be based on disease biology, number of prior regimens, time since initiation of therapy, and regimen efficacy. Current imaging recommendations are not data-based and do not adjust for new agents that have been approved. Oncologists should integrate these into individualized estimates to determine optimum frequency of imaging in clinical practice and research. [Table: see text]

Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications.

Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.

Dysbiosis and Restoration Dynamics of the Gut Microbiome Following Therapeutic Exposure to Florfenicol in Snubnose Pompano (Trachinotus blochii) to Aid in Sustainable Aquaculture Production Strategies.

Information on unintended effects of therapeutic exposure of antibiotics on the fish gut microbiome is a vital prerequisite for ensuring fish and environmental health during sustainable aquaculture production strategies. The present study forms the first report on the impact of florfenicol (FFC), a recommended antibiotic for aquaculture, on the gut microbiome of snubnose pompano (Trachinotus blochii), a high-value marine aquaculture candidate. Both culture-dependent and independent techniques were applied to identify the possible dysbiosis and restoration dynamics, pointing out the probable risks to the host and environment health. The results revealed the critical transient dysbiotic events in the taxonomic and functional metagenomic profiles and significant reductions in the bacterial load and diversity measures. More importantly, there was a complete restoration of gut microbiome density, diversity, functional metagenomic profiles, and taxonomic composition (up to class level) within 10–15 days of antibiotic withdrawal, establishing the required period for applying proper management measures to ensure animal and environment health, following FFC treatment. The observed transient increase in the relative abundance of opportunistic pathogens suggested the need to apply proper stress management measures and probiotics during the period. Simultaneously, the results demonstrated the inhibitory potential of FFC against marine pathogens (vibrios) and ampicillin-resistant microbes. The study pointed out the possible microbial signatures of stress in fish and possible probiotic microbes (Serratia sp., Methanobrevibacter sp., Acinetobacter sp., and Bacillus sp.) that can be explored to design fish health improvisation strategies. Strikingly, the therapeutic exposure of FFC neither caused any irreversible increase in antibiotic resistance nor promoted the FFC resistant microbes in the gut. The significant transient increase in the numbers of kanamycin-resistant bacteria and abundance of two multidrug resistance encoding genes (K03327 and K03585) in the treated fish gut during the initial 10 days post-withdrawal suggested the need for implementing proper aquaculture effluent processing measures during the period, thus, helps to reduce the spillover of antibiotic-resistant microbes from the gut of the treated fish to the environment. In brief, the paper generates interesting and first-hand insights on the implications of FFC treatment in the gut microbiome of a marine aquaculture candidate targeting its safe and efficient application in unavoidable circumstances. Implementation of mitigation strategies against the identified risks during the initial 15 days of withdrawal period is warranted to ensure cleaner and sustainable aquaculture production from aquatic animal and ecosystem health perspectives.

Unleashing the full potential of cell therapy through RNA engineering

The US Food and Drug Administration has approved Chimeric Antigen Receptor (CAR)-transduced T-cells (CAR-T cells) for the treatment of relapsed/refractory B-cell malignancies and multiple myeloma, ushering in a novel therapeutic modality that uses genetically engineered living cells as therapeutic drugs. CAR-T cell therapies on the market today are engineered by inserting CAR genes into the genome of cells using a virus. DNA-engineered cells maintain the therapeutic activity throughout their life because they are permanently modified. Further, their daughter cells carry the altered gene as the cells proliferate. In some types of relapsed/refractory blood cancers, this approach has been effective, though safety concerns remain. DNA-engineered cells carry a high chance of severe toxicity as there is not a natural ‘off-switch’ if the cells over-expand or otherwise exhibit off-target toxicity. Indeed, patient deaths have occurred due to uncontrolled proliferation of CAR-T cells. Therefore, all patients receiving CAR-T cell treatments must be strictly monitored for both short-term and long-term toxicity. This restricts the use of DNA-engineered cells only to patients with imminently fatal diseases like relapsed cancer that is refractory standard of treatment. A solution is to engineer cells with RNA rather than DNA. RNA does not integrate into the genome and has a measurable natural half-life, effectively limiting the duration and magnitude of therapeutic exposure. A defined half-life also informs the clinical protocol design for adjusting the dose and schedule of treatment to minimize toxicities. Therefore, RNA Cell Therapy is expected to provide safer alternatives without requiring cumbersome monitoring programs, and to allow the expansion of engineered cell therapies into indications beyond advanced cancer. In fact, RNA engineered CAR-T cell therapies are already being tested in an autoimmune disease (i.e., NCT04146051) as well as newly diagnosed cancer (i.e., NCT04816526). Other indications will quickly follow as safety experience with RNA Cell Therapy accumulates and new technologies make it possible to transfect billions of primary cells with one or more RNAs. In particular, the ability to engineer various cell types with multiple RNAs will lend itself to the design of novel combination products, a capacity that will be highly useful to treat complex diseases. This Expert Insight article reviews historical milestones that paved the way to the development of RNA Cell Therapy products now in clinical trials. Three examples of active clinical trials are described to show the transformative possibilities of engineering cells with RNA.

Patient Pain Experiences and the Emergency Department Encounter: A Qualitative Analysis

BackgroundLegislation, practice recommendations, and the likely link between therapeutic opioid exposure and iatrogenic opioid use disorder (OUD) have led to reduced opioid prescribing. The effects of this change on unrelieved pain and the overdose crisis are not well-characterized. AimWe explored emergency department (ED) patients’ beliefs and experiences involving pain and emergency care to inform the development of future psychosocial interventions that balance the need for acute pain management with risks from opioid exposure. MethodsQualitative, semi-structured interviews were conducted after discharge from an urban, academic Level 1 trauma center ED from September 2020 to May 2021 with 18 adult patients presenting with acute pain. After transcription of audio recording, common themes were identified using framework analysis. Thematic hierarchy was validated with Pearson correlation coefficients for cluster analysis of word similarity. ResultsOf the 18 participants, most were Black (n = 11, 61%) and male (n = 12, 66.7%). Analysis identified one overarching theme: locus of control with an emergency pain encounter. Four themes were identified surrounding internal and external influences on pain management: (1) accessing healthcare for acute pain; (2) managing the pain after discharge; (3) seeking opioids: self-medicating and misuse; and (4) opioid crisis makes people in pain suffer. ConclusionsPatients discharged from the ED reported unrelieved pain, factors that influence their pain management, and an ability to seek opioids from non-medical sources. There is a significant disconnect between patients and providers in terms of priorities in pain management and the importance of individualized care.

An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients.

Background and ObjectivesAlthough dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.MethodsIn this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.ResultsA combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.ConclusionsA regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.ClinicalTrials.gov identifierNCT03738683.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01113-6.