Dosing Regimens Research Articles

Review on Oral Osmotic Tablet

Traditional oral medication delivery methods provide the drug with an immediate release and an efficient concentration at the intended location. Such a dosage regimen could lead to unexpected, ever-changing plasma concentrations. As a result, numerous regulated medication delivery systems are created. Among these, osmotic drug delivery systems (ODDS) and pulsatile drug delivery systems (PDDS) are becoming more and more significant because they improve patient treatment efficacy and compliance by delivering the medicine at precise times based on the course and physiological requirements of the disease. They regulate the drug’s delivery by using the osmotic pressure theory.To a significant extent, the drug’s release is unaffected by GIT physiological variables. Both targeted and systemic medication delivery are possible with these methods. The theoretical idea of drug delivery, various oral osmotic drug delivery system types, factors influencing the drug delivery system, benefits and drawbacks of these delivery systems, fundamental osmotic system components, evaluation parameters, difficulties, and emerging technologies in oral controlled drug delivery are all “highlighted” in this review.

Current status of drug therapy for alveolar echinococcosis

Alveolar echinococcosis (AE) is a chronic zoonotic parasitic disease caused by infection with Echinococcus multilocularis . AE is associated with a high mortality rate and poses a significant threat to human health. The primary treatment for AE is surgical resection of the lesions; however, owing to its long incubation period and insidious disease progression, many patients are diagnosed only after the onset of complications such as liver cirrhosis, jaundice, and portal hypertension, which preclude curative surgical intervention. For patients who are unwilling or unable to undergo surgery, lifelong administration of anti-AE medications is necessary. Benzimidazole compounds, such as albendazole and mebendazole, are the current mainstays of treatment, offering good efficacy. Nevertheless, these medications primarily inhibit parasite proliferation rather than eradicate the infection, and their long-term use can lead to significant drug-related toxic effects. Consequently, there is an urgent need to develop new therapeutic strategies that convey better efficacy and reduce the adverse effects associated with current treatments. Recent advancements in AE therapy include novel synthetic compounds such as antiviral agents, antibiotics, antineoplastic agents, immunosuppressants, and antiangiogenic agents, as well as natural compounds derived from traditional Chinese and Tibetan medicine. These new drugs show promising clinical potential because they interfere with parasitic metabolic pathways and cellular structures. This review aims to discuss recent research on AE drug therapy, including mechanisms of action, dosing regimens, signalling pathways, and therapeutic outcomes, with a goal of providing new insights and directions for the development of anti-AE drugs and summarizing current advancements in AE pharmacotherapy.

Half-life-extended Monoclonal Antibody APG777 for Atopic Dermatitis: Design of the Phase 2 APEX Study

Introduction: Current treatments for moderate-to-severe atopic dermatitis (AD) include topical and systemic therapies. The latter includes monoclonal antibodies (mAbs) targeting the IL-13 pathway, which is implicated in AD pathophysiology. While currently available mAbs directed against the IL-13 pathway have demonstrated efficacy for AD, they require ongoing injections every 2 or 4 weeks. APG777 is a humanized, anti-IL-13 mAb that binds IL-13 and blocks downstream signaling mediated by the IL-13Rα1/IL-4Rα complex. APG777 contains amino acid modifications designed to extend plasma half-life through increased FcRn-mediated antibody recycling. Interim results from an ongoing phase 1 study in healthy participants suggest a favorable safety and PK/PD profile for APG777, and a half-life of approximately 75 days. Methods: APEX (NCT06395948) is a 2-part, multicenter, phase 2, randomized, double-blinded, placebo-controlled clinical trial evaluating the efficacy and safety of APG777 in adults with moderate-to-severe AD. Adults (≥18 years of age) are eligible to participate if they have a diagnosis of AD for ≥1 year prior to screening and exhibit moderate-to-severe AD (EASI ≥16, IGA ≥3, BSA ≥10%) at both screening and baseline visits. Part A of the study (proof-of-concept) is evaluating the efficacy and safety of one induction dose regimen of APG777 compared with placebo over 16 weeks; this is followed by a 36-week maintenance period. Part B (dose-regimen finding) will evaluate different dose regimens of APG777 compared with placebo over 16 weeks followed by a 36-week maintenance period. Participants completing the maintenance period of Part A or B of the study will be eligible to enroll in a separate long-term extension study or enter the post-treatment follow-up period (up to 52 weeks). The primary outcome measure for the study is the percentage change from baseline to week 16 in the Eczema Area and Severity Index (EASI). The APEX study is currently enrolling.

Results of a Phase 2 Multicenter Study to Evaluate the Efficacy of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction: VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective: In Part 2 of this study, the secondary objective was to evaluate the effect of various dosing regimens on the antitumor efficacy of VP-315 in a larger population of adult subjects with biopsy proven BCC. Methods: Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Efficacy endpoints included histological clearance of target tumor(s) and estimate of remaining tumor volume (tumor size reduction) at excision (Week 12-13). Results: Eighty-two (82) subjects (n=92 lesions) completed treatment for BCC with VP-315 in Part 2. Approximately 51% of tumors achieved complete histologic clearance. All tumors treated had a reduction in tumor size. Overall tumor size reduction was 86%. Tumor size reduction in subjects who still had any residual tumor was 71%. Conclusion: Complete histological clearance in a majority of VP-315 treated tumors could eliminate the need for surgical intervention in those patients in clinical practice. In subjects with residual tumor burden, the substantial reduction in tumor size after VP-315 treatment would markedly reduce the surgical incision area and the amount of potential post-surgical scarring. Based on the favorable results, further research using VP-315 as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting is warranted.

Bimekizumab 4-year Maintenance of Responses in Week 16 Responders with Moderate to Severe Plaque Psoriasis: Results from the BE BRIGHT Open-label Extension Phase 3 Trial

Introduction: Psoriasis is a chronic disease where loss of response to biologic therapies over time is commonly observed; studying long-term efficacy of new treatments is important.1 Maintenance of high responses to bimekizumab (BKZ) has been reported through 3 years (yrs) in patients with moderate to severe plaque psoriasis.2 This study evaluates the maintenance of clinical responses over 4 years among patients with moderate to severe plaque psoriasis who achieved complete or near-complete skin clearance after 16 weeks (wks) of BKZ treatment and entered the BE BRIGHT open-label extension. Responses were compared over 4 years between all patients who were randomized to BKZ and continued to receive bimekizumab (320 mg every 4 wks [Q4W] or Q8W) in the open-label extension, and those who received the BKZ dosing regimen that is approved for most patients: BKZ 320 mg Q4W to Wk 16 followed by 320 mg Q8W. Methods: Patients completing the 52-wk BE VIVID or 56-wk BE SURE/BE READY phase 3 trials could enter the BE BRIGHT open-label extension (OLE).2–5 Maintenance of PASI90/PASI100 (≥90%/100% improvements from baseline in Psoriasis Area and Severity Index) to Yr4 (OLE Wk144) was assessed in Wk16 responders. Analyzed patients were randomized to BKZ 320 mg Q4W to Wk16, received BKZ Q4W or Q8W until OLE entry, then BKZ Q4W or Q8W dependent on PASI response/prior dose (BKZ Total); the subset who received BKZ Q4W/Q8W/Q8W (initial/maintenance/OLE) were also analyzed. All received BKZ Q8W from OLE Wk48 or at their next scheduled visit. Patients who discontinued due to lack of efficacy/treatment-related adverse events were considered non-responders; multiple imputation was used for all other missing data (modified non-responder imputation). Results: Of 989 BKZ-randomized patients, 87.5% achieved PASI90 and 62.7% PASI100 at Wk16 (non-responder imputation). 693 Wk16 PASI90 and 503 PASI100 responders entered the OLE (BKZ Total); 186 and 147, respectively, received BKZ Q4W/Q8W/Q8W. 87.7%/73.3% of Wk16 PASI90/PASI100 responders maintained their responses to Yr4 (BKZ Total). In the Q4W/Q8W/Q8W subset, 89.0%/76.7% maintained their responses to Yr4. Conclusions: Among Wk16 responders, high efficacy responses were sustained through 4 yrs of BKZ treatment, including patients who received the approved Q4W/Q8W/Q8W dosing regimen.

Spesolimab decreases generalized pustular psoriasis (GPP) body surface area (BSA) over time: Results from the EFFISAYIL® 2 trial

Generalized pustular psoriasis (GPP) is a chronic inflammatory, potentially life-threatening skin disease. Most patients experience chronic skin symptoms between flares which can lead to significant patient burden. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved in the United States to treat GPP in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. EFFISAYIL® 2 (NCT04399837) evaluated the efficacy and safety of subcutaneous (SC) spesolimab in GPP. Here, we report the effects on GPP body surface area (BSA) over time in patients treated with the FDA approved spesolimab dosing regimen (600 mg loading dose, then 300 mg maintenance dose every 4 weeks) in EFFISAYIL® 2. Total BSA was determined based on a weighted average of the extent of involvement over 4 main body regions, with head = 10%, upper extremities = 20%, trunk = 30%, and lower extremities = 40%. Total BSA involvement was calculated for each subject at 4 timepoints (baseline, Week 4, Week 16, and Week 48). Data collected closest to the given time points were used by including the effect of potential intravenous spesolimab treatment and subsequent open-label SC spesolimab treatment in patients who experienced a flare. The data were analyzed as observed. Total BSA improved continuously under spesolimab treatment (13.3% at baseline, 10.6% at Week 4, 9.4% at Week 16, ending at 4.5% at Week 48). Continuous treatment with spesolimab SC improved BSA from 13% to 5% at the end of the trial. These findings suggest a role of spesolimab in improving area of involvement as measured by BSA.

Spesolimab decreases generalized pustular psoriasis (GPP) body surface area (BSA) over time in patients switching from conventional systemic treatments: Results from the EFFISAYIL® 2 trial

Generalized pustular psoriasis (GPP) is a chronic inflammatory, potentially life-threatening skin disease. Most patients experience chronic skin symptoms between flares which can lead to significant patient burden. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved in the United States to treat GPP in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. EFFISAYIL® 2 (NCT04399837) evaluated the efficacy and safety of subcutaneous (SC) spesolimab in GPP. Here, we report the effects on GPP body surface area (BSA) over time in patients switched from a small-molecule systemic therapy at randomization when treated with the FDA approved spesolimab dosing regimen (600 mg loading dose, then 300 mg maintenance dose every 4 weeks) in EFFISAYIL® 2. Total BSA was determined based on a weighted average of the extent of involvement over 4 main body regions, with head = 10%, upper extremities = 20%, trunk = 30%, and lower extremities = 40%. Total BSA involvement was calculated for each subject at 4 timepoints (baseline, Week 4, Week 16, and Week 48). Data collected closest to the given time points were used by including the effect of potential intravenous spesolimab treatment and subsequent open-label SC spesolimab treatment in patients who experienced a flare. The data were analyzed as observed. Within the FDA approved spesolimab regimen group, the average BSA for patients who stopped a systemic medication for GPP (Total N=22; acitretin = 13, cyclosporine = 7, methotrexate = 1, acitretin/methotrexate = 1) was 11.1 at baseline, decreasing to 8.2 at Week 4, 6.4 at Week 16, and then ending at 3.6 at Week 48. Total BSA involvement decreased over the 48 weeks of the trial in spesolimab-treated patients who stopped an off-label systemic medication for GPP at randomization.

Spesolimab decreases generalized pustular psoriasis (GPP) body surface area (BSA) over time in patients with various lengths of disease history: Results from the EFFISAYIL® 2 trial

Generalized pustular psoriasis (GPP) is a chronic inflammatory, potentially life-threatening skin disease. Most patients experience chronic skin symptoms between flares which can lead to significant patient burden. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved in the United States to treat GPP in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. EFFISAYIL® 2 (NCT04399837) evaluated the efficacy and safety of subcutaneous (SC) spesolimab in GPP. Here, we report the effects on GPP body surface area (BSA) over time in patients diagnosed <5 vs ≥5 years prior to enrollment when treated with the FDA approved spesolimab dosing regimen (600 mg loading dose, then 300 mg maintenance dose every 4 weeks) in EFFISAYIL® 2. Total BSA was determined based on a weighted average of the extent of involvement over 4 main body regions, with head = 10%, upper extremities = 20%, trunk = 30%, and lower extremities = 40%. Total BSA involvement was calculated for each subject at 4 timepoints (baseline, Week 4, Week 16, and Week 48). Data collected closest to the given time points were used by including the effect of potential intravenous spesolimab treatment and subsequent open-label SC spesolimab treatment in patients who experienced a flare. The data were analyzed as observed. Within the FDA approved regimen spesolimab group, average BSA for patients diagnosed with GPP for <5 years (N=13) was 14.7 at baseline, 15.0 at Week 4, then decreasing to 11.7 at Week 16, and then to 5.0 at Week 48. For patients diagnosed with GPP for ≥ 5 years (N=17) the values were 12.3 at baseline, decreasing to 7.0 at Week 4, increasing slightly to 7.6 at Week 16, and decreasing to 4.1 at Week 48. Total BSA involvement decreased over the 48 weeks of the trial in spesolimab-treated patients regardless of whether they were early (< 5 years) or late (≥ 5 years) in their disease course. This finding demonstrates the efficacy of spesolimab in controlling GPP consistently for patients with various lengths of disease history.

Four-weekly dosing intervals with subcutaneous spesolimab appear to be required for optimal prevention of generalized pustular psoriasis flares: Data from the EFFISAYIL® 2 and EFFISAYIL® ON trials

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Results of a Phase 2 Multicenter Study Evaluating the Safety and Tolerability of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective In Part 2 of this study, the primary objective was to determine the optimal dosing regimen for VP-315 by exploring the effects of various dosing schemes on the safety and tolerability of VP-315 in a larger population of subjects with biopsy proven BCC. Methods Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Safety and tolerability were assessed by documenting the occurrence of Treatment Related Adverse Events (TRAEs), including those of special interest, Treatment Related Serious Adverse Events (TRSAEs), discontinuations due to AEs and expected treatment-related cutaneous reactions including tumor necrosis. Results All 82 subjects completed one of the VP-315 treatment regimens for BCC. TRAEs were mostly mild to moderate. AEs included injection site pain (mild 13.4%, moderate 12.2%, severe 1.2%), hypertension (mild 4.9%), hypotension (mild 4.9%), erythema (mild 1.2%, moderate 2.4%), and headache (mild 2.4%). Expected cutaneous reactions were observed. No TRSAEs were reported. Conclusion VP-315 treatment was shown to be safe and well-tolerated when administered once daily 2-3 times per week per tumor for up to 2 weeks using a split dose approach. Given its favorable safety profile, VP-315 warrants continued research as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting. Sponsored by Verrica Pharmaceuticals Inc.

Spesolimab increases the percentage of generalized pustular psoriasis (GPP) patients with clear skin over time as measured by the Physician’s Global Assessment for GPP (GPPGA): Results from the EFFISAYIL® 2 trial

Generalized pustular psoriasis (GPP) is a chronic inflammatory, potentially life-threatening skin disease. Most patients experience chronic skin symptoms between flares which can lead to significant patient burden. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved in the United States to treat GPP in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. EFFISAYIL® 2 (NCT04399837) evaluated the efficacy and safety of subcutaneous (SC) spesolimab in GPP. Here, we report the percentage of patients achieving clear skin (Physician’s Global Assessment for GPP [GPPGA]=0)1 over time from patients who were treated with the FDA approved spesolimab dosing regimen (600 mg loading dose, then 300 mg maintenance dose every 4 weeks) in EFFISAYIL® 2. Measurements were completed for each subject at 4 timepoints (baseline, Week 4, Week 16, and Week 48). The data were analyzed as observed. Proportion of patients with GPPGA total score of 0 increased over time under spesolimab treatment (10.0% (N=3/30) at baseline, 27.6% (N=8/29) at Week 4, 48.1% (N=13/27) at Week 16, and 52.2% (N=12/23) at Week 48). Continuous treatment with spesolimab SC improved skin symptoms in GPP, with 50% of patients achieving clear skin at Week 48. These findings suggest a role of spesolimab in complete resolution of GPP skin symptoms.

External evaluation of neonatal vancomycin population pharmacokinetic models: Moving from first-order equations to Bayesian-guided therapeutic monitoring.

Guidelines for vancomycin therapeutic monitoring recommend using a Bayesian approach with a population pharmacokinetic model to estimate the 24 h area under the concentration-time curve over first-order equations. Thus, we performed an external evaluation of population pharmacokinetic models of vancomycin in neonates and compared Bayesian results with those observed in clinical practice via pharmacokinetic equations to improve therapeutic monitoring by proposing optimized initial dosing nomograms and assessing the feasibility of reduced blood sampling strategies using the most predictive models. Models were identified from the literature and evaluated via an external neonatal population. A priori predictive performance was first assessed by prediction-based diagnostics, then by simulation-based diagnostics and a posteriori analyses only if deemed satisfactory; model-informed vancomycin exposure was also compared with reference first-order pharmacokinetic equations. The best-performing models were ultimately subjected to Monte Carlo simulations to develop new initial dosing nomograms offering the highest probability of achieving therapeutic target. A total of 28 population pharmacokinetic models were evaluated in the external dataset, which includes 72 neonates and 380 vancomycin concentrations. Eleven models had an adequate predictive performance with bias ≤ ± 15% and imprecision 30%, while the Bayesian approach yielded over 75% agreement with reference exposure values in most cases. Nonetheless, Capparelli etal. and Mehrotra etal. models performed the best overall, showing the lowest imprecisions of 16.8% and 16.9%, respectively; both models recommended higher dosage regimens than the theoretical nomogram currently applied to favor therapeutic target attainment. We externally evaluated numerous neonatal population pharmacokinetic models of vancomycin and used the most predictive ones to advocate new initial dosing nomograms. Clinical implementation of the Bayesian approach could reduce the time needed to reach therapeutic target and limit the number of blood samples in newborns compared with traditional pharmacokinetic equations.

The distinctive pharmacokinetic profile of rezafungin, a long-acting echinocandin developed in the era of modern pharmacometrics.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

Reevaluating antibiotic prophylaxis: insights from a network meta-analysis on dry socket and surgical site infections.

Three databases (MEDLINE, Cochrane Library, and Scopus) were searched in December 2021 for 16 Randomised Clinical Trials (RCTs). Three reviewers reviewed the articles on oral antibiotic prophylaxis (ABP) for the prevention of surgical site infection (SSI) and dry socket (DS) after lower third molar (L3M) extraction using the PICO framework. From 1999 to 2021, RCTs involving healthy patients undergoing L3M extraction with ABP, placebo, or no therapy were included. Adverse effects (AEs) associated with antibiotic usage, along with the main outcomes (DS and SSI), were also documented. Three independent investigators selected articles based on pre-established inclusion criteria, with any disagreements resolved by consensus or additional researchers. PRISMA guidelines were followed, involving initial title and abstract screening, followed by full-text evaluation. Exclusion reasons were documented, and the most recent report was included when multiple reports on the same patients were found, with no language restrictions applied. Two investigators evaluated studies quality and quality of evidence respectively using the Cochrane Collaboration tool and GRADEpro GDT. They independently extracted data, focusing on the type of extraction and the number of extracted L3M. They also detailed the use of antibiotics, including dosage, dosage regimen, timing, and duration. Among 16 articles, 15 used a parallel arm design, while one used a crossover design. The antibiotics studied included Amoxicillin+Clavulanic acid (7 articles), Amoxicillin (6), Metronidazole (2), Azithromycin (1), and Clindamycin (2), all compared with no treatment or placebo. A pairwise meta-analysis was used to combine studies with equivalent treatment (direct estimation), and a network meta-analysis compared outcome variables across different treatments (indirect comparison). Two included articles had a low risk of bias and the level of evidence was low according to GRADE. Pooled results supported the use of antibiotics to reduce DS and SSI following L3M extraction with a number needed to treat 25 and 18, respectively. Despite the fact that ABP reduces the risk of DS and SSI, it is recommended to consider systemic conditions and individual patient risk factors before prescribing antibiotics, due to global health threat.

Pharmacokinetics, Efficacy, and Safety of Upadacitinib in Pediatric Patients with Polyarticular-Course Juvenile Idiopathic Arthritis: An Interim Analysis of an Open-label, Phase 1 Trial.

This work aimed to evaluate the pharmacokinetics, efficacy, and safety of upadacitinib, an oral selective JAK inhibitor, in pediatric patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). In an open-label, phase 1 study (SELECT-YOUTH), enrolled patients, aged 2 to <18 years with pcJIA, received bodyweight-based upadacitinib doses using a twice-daily (BID) oral solution or once-daily (QD) extended-release tablet based on their body weight and ability to swallow tablets. The study included a 7-day pharmacokinetic assessment, followed by a long-term efficacy and safety evaluation for up to 156 weeks, including an additional long-term safety cohort. This interim analysis included available pharmacokinetic and safety data and efficacy data collected through Week 48. A total of 57 patients received upadacitinib. The median time to maximum upadacitinib concentration was approximately 3 hours and 1 hour for the tablet and oral solution regimens, respectively; the harmonic mean functional half-life was approximately 5 hours and 2 hours, respectively. Juvenile idiopathic arthritis (JIA) American College of Rheumatology (ACR)30/50/70/90/100 responses at Week 12 were 91.8/89.8/69.4/49.0/32.7%, respectively. Efficacy was generally maintained through Week 48, and improvement in additional efficacy endpoints was also observed. At a median exposure duration of 412 days, 52 of 57 patients reported adverse events, of these 6 experienced serious adverse events. Adverse events were predominately mild to moderate in severity and consistent with the known safety profile of upadacitinib. This interim analysis demonstrates that the bodyweight-based dosing regimen of upadacitinib was well tolerated and efficacious in pediatric patients with pcJIA.

Long-Term Disease-Free Survival and Health-Related Quality of Life Results of High-Dose-Rate Brachytherapy as Monotherapy for Low and Intermediate-Risk Prostate Cancer Treated in a Community Cancer Centre

To determine the long-term disease-free survival, long-term toxicity, and effect on health-related quality of life of a two-fraction regimen of high-dose-rate (HDR) prostate brachytherapy. Patients with low- or intermediate-risk prostate cancer were treated with CT-planned HDR brachytherapy as monotherapy in two implants of 13.5 Gy in one community cancer center. Prostate-specific antigen (PSA), International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC) questionnaires were evaluated at each follow-up visit. Biochemical recurrence (Phoenix definition) was evaluated to determine disease-free survival at 5 and 7 years. Proportion of patients in each IPSS category (mild = 0-7, moderate = 8-18, severe = 19+) was evaluated at each follow-up interval. Thirty patients were accrued to the study between 2014 and 2016. Median prostate-specific antigen was 8,7 (range 4.1-17.5). T stages were T1c = 65%, T2a = 21%, and T2b = 14%. Twenty-seven percent of patients had a Gleason score of 6 and 73% had a Gleason score of 7. 13% were in low risk category and 87% in intermediate risk category. Median follow-up was 84 months. There were no deaths at 84 months after brachytherapy. Disease-free survival was 90% at 5 years and 86% at 7 years. Two patients experienced late Grade 3 GU toxicity (6.6%). This study serves as proof of concept that HDR monotherapy can be performed successfully with excellent long-term outcomes in a community cancer center with adequate training and experience. The long-term disease-free survival rate and the health-related quality of life seem acceptable as compared to other treatment modalities. Further study is ongoing with regard to the optimal dosing regimen for HDR monotherapy.

Exposure-Response Analyses of Sacituzumab Govitecan Efficacy and Safety in Patients With Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVGSG) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVGSG. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVGSG was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.

Ocular Pharmacokinetics of Faricimab Following Intravitreal Administration in Patients With Retinal Disease.

To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints. A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was ∼6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens. Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen. The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t1/2 alone.

The Utilization of the Accelerated Approval Pathway in Oncology: A Case Study of Pembrolizumab.

The accelerated approval (AA) pathway was established by the United States Food and Drug Administration (FDA) to provide earlier access to therapies for patients with serious medical conditions and unmet medical needs. Since its inception, the AA pathway has been used for novel treatments across different therapeutic areas, but most prominently in oncology, including the immune checkpoint inhibitor class. This review article describes the history of regulatory approvals for pembrolizumab, an immunotherapy agent targeting programmed death receptor-1 (PD-1), and use of the AA pathway and the corresponding regulatory decisions made by the FDA. From its first AA in September 2014 to February 2024, pembrolizumab has used the accelerated pathway for roughly 40% of the approved indications listed in the US Prescribing Information and was the first oncology therapy to receive an AA for an alternate dosing regimen and a tissue-agnostic indication. As of February 2024, 14 of the 18 indication-specific AAs and 1 post-marketing requirement (PMR) for the alternate dosing regimen AA were converted to traditional approvals. Accelerated approvals for two indications were withdrawn, and the remaining ongoing PMRs are not due until later in 2024 or 2025. The median conversion time from AA to traditional approval was 2.6 years, which is roughly 6 months earlier than the median time reported for oncology AAs. While FDA was the first agency to establish an expedited approval pathway, regulators from other countries have established similar pathways. For pembrolizumab, approximately half of the datasets that supported US AAs also supported expedited approval, or sometimes full approval, in Canada, EU, Australia or Japan. Ultimately, the AA pathway balances the provision of earlier access to therapies with overcoming uncertainty about potential effectiveness, and therefore it is important to confirm treatment benefit and withdraw indications that do not confirm benefit in a timely manner. The regulatory strategy and use of this expedited program for pembrolizumab highlights the importance of the AA pathway in providing oncology patients with earlier access to life-saving medications.

OGC SO08 - Optimising Analgesia in Sub-total Oesophagectomy: A Dose of Success

Abstract Background Sub-total oesophagectomy (STO) is a complex and major surgery with significant associated burdens for our patients. Our centre in North-East England completes 70-80 STOs annually. In the peri-operative period, good analgesia management and delivery is key. Analgesia strategy has evolved across the UK over the past decade, influenced by multi-modal analgesia, progressing surgical approaches towards minimally invasive operations alongside the ongoing drive for enhanced recovery programmes endorsing early mobilisation. Surgical approach in our patient cohort now comprises a combination of Open-Open, combined Open-Minimally invasive and entirely minimally invasive techniques. Our analgesia strategy combines single shot intrathecal diamorphine and regional anaesthesia. Method We engaged our multi-professional (Acute Pain Specialist Nurses, Anaesthesia Consultants and Surgical Consultants) team in a PDSA cycle. A guidance analgesia package was agreed after review of retrospective cases. This package was delivered to our baseline group of 10 patients. We used subjective patient reported abdominal and thorax pain scores on a 0-10 scale, recorded by our pain team each day for post-operative days 1-5. Following analysis, we implemented a single change to Intrathecal diamorphine dosing - changing from uniform delivery of 1000micrograms intrathecal diamorphine to a dose calculated on Ideal Body Weight of 15-20micrograms/kg up to 1500micrograms maximum dose Results Our baseline group of 10 patients all received 1000micrograms of intrathecal diamorphine - mean dose 15.9mcg/kg. Our intervention group of 12 patients received doses based upon their ideal body weight - mean dose 18.9mcg/kg. Overall, there was a trend of reduced pain scores following our intervention. Thoracic reported overall pain scores were significantly lower (p=0.04) following the intervention. No significant difference was demonstrated specifically in the first 24 or 48hours in overall, abdominal or thoracic pain scores. Importantly, there were no reported adverse events related to our higher dosing regime and no recorded side effects such as pruritis or nausea. Conclusion There is little evidence with regards the use of higher dose intrathecal diamorphine in the literature. The sample sizes in our groups are small but overall reduction in patient reported pain scores appear to be associated with use of the higher dose of intrathecal diamorphine, based upon ideal body weight and importantly without any adverse effect. Continued evolution of our analgesia strategies is essential alongside that of surgical techniques. The next iterations of our guidance and PDSA cycle will consider our regional techniques to identify if further advances can be made.