Drug Levels Research Articles

Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial. The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated. The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA). The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD. https://clinicaltrials.gov/study/NCT04693520 .

A Wireless Operated Flexible Bioelectronic Microneedle Patch for Actively Controlled Transdermal Drug Delivery.

Precise control over drug release rates is critical for enhancing therapeutic efficacy, reducing side effects, and maintaining stable drug levels. While microneedles (MNs) offer a promising approach for transdermal drug delivery, conventional passive-response systems often lack adaptability across diverse drugs and disease models, limiting their versatility. Here, this work presents a flexible bioelectronic microneedle patch (FBMP) that integrates flexible electronics for actively controlled transdermal delivery. The FBMP incorporates a flexible printed circuit board (FPCB), a eutectic gallium-indium (EGaIn) heating film, and dual-layer microneedles with a polyvinyl alcohol (PVA) core and polycaprolactone (PCL) shell. This configuration allows real-time adjustment of the thermal response rate via smartphone-controlled Bluetooth, achieving rapid drug release within 2 min or sustained release over 10 h. In various animal models, the FBMP demonstrate versatility in delivering multiple drug types, optimizing efficacy, and minimizing side effects for both acute and chronic conditions. Overall, this work introduces a flexible, universal electronic microneedle platform with significant potential to advance precision and personalized medicine by enabling customizable, actively controlled drug release.

Sclerotic Bone Adversely Affects Anti-Tuberculosis Drug Distribution in Patients with Spinal Tuberculosis: A Prospective Cross-Sectional Study.

The effects of sclerotic bone on anti-tuberculosis (anti-TB) drug distribution in the blood and in spinal tuberculosis (STB) lesions were investigated. Fifty-six patients with STB were prospectively enrolled from January 2020 to March 2023 and were divided into 2 groups: a group with sclerotic bone and a group without sclerotic bone, as identified on preoperative computed tomography (CT) scans. Individuals in the sclerotic bone group were further divided into fragmentary and non-fragmentary sclerotic bone groups. The patients underwent surgery, and blood was collected along with normal vertebral and STB-lesion-containing bone tissue samples. Following treatment, the samples were processed by a pharmacological laboratory in order to detect the concentrations of anti-TB drugs, including pyrazinamide, rifampicin, isoniazid, and ethambutol. Twenty-seven East Asian female and 29 East Asian male patients with STB were included in this study. The levels of anti-TB drugs showed a progressive decrease with increased circulatory distance, from blood to normal vertebral tissue to TB lesions, across all patient groups. Drug concentrations in TB lesions in the sclerotic bone group were significantly lower than those in the non-sclerotic bone group, as were concentrations in TB lesions in the non-fragmentary sclerotic bone group relative to those in the fragmentary sclerotic bone group. Drug levels in the blood and in normal vertebral bone tissue did not significantly differ between the sclerotic and non-sclerotic groups, nor between the fragmentary and non-fragmentary groups. Drug levels in the blood were linearly correlated with those in TB lesions in both the non-sclerotic bone group and the fragmentary sclerotic bone group. These results indicate that sclerotic bone negatively affects the dissemination of anti-TB drugs, with non-fragmentary sclerotic bone posing a greater obstacle than fragmentary sclerotic bone. In patients with STB without sclerotic bone or with fragmentary sclerotic bone, anti-TB drug levels in the blood were linearly correlated with drug levels in STB lesions. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Clinical value of saliva therapeutic drug monitoring of newer antiseizure medications.

Saliva is a promising option for therapeutic drug monitoring, with studies since the 1970s indicating a good correlation between plasma and saliva levels for early anti-seizure medications, although limited data exist for newer generation drugs. To evaluate the reliability and predictive power of saliva as a minimally invasive surrogate marker of plasma concentration for the routine therapeutic drug monitoring (TDM) of newer anti-seizure medications (ASM). We collected blood samples at steady state in patients at least 6 h post-dose, paired with unstimulated saliva samples. We evaluated the correlation between plasma and saliva drug levels and the positive and negative predictive value for plasma values extrapolation from saliva levels. A very low saliva level was defined as below half the plasma lower reference limit. 294 adult patients (53 % male) with a mean age of 40 (SD: 16) were enrolled and 589 paired saliva-plasma samples were quantified. The highest significant correlations between saliva and plasma were observed for zonisamide (R2: 0.92) perampanel (0.91), brivaracetam (0.87), followed by topiramate, lamotrigine, lacosamide (0.76-0.68), and rufinamide, levetiracetam, pregabalin (0.63-0.55). No significant correlation was found for the active mono-hydroxy derivative of oxcarbazepine. Despite a good correlation coefficient, the correlations between saliva and plasma levels were generally loose, resulting in a broad predicted range of plasma levels for a given saliva level. Nonetheless, very low saliva levels exhibited strong specificity in predicting low plasma levels, with 87 % to 100 % accuracy, and when saliva levels fell below the limit of quantification, all corresponding plasma levels were below reference ranges. This large newer ASM paired plasma-saliva collection allows to precise the potential use of saliva in the management of epilepsy, especially for commonly used ASM such as lamotrigine and levetiracetam. Although they correlate well, extrapolating plasma levels from saliva samples is still an imprecise approximation, making it inadequate for fine dosage adjustments. Yet, a very low saliva level has an appreciable discriminative ability for low plasma level. Unstimulated saliva represents a convenient non-invasive alternative to plasma, to readily identify compliance issues or major drug-drug interactions.

Precision Therapy for Prostate Cancer: Advancements in Polymeric Nanocarrier Systems.

Prostate cancer is a major worldwide health concern, and existing treatments often face challenges such as drug resistance, systemic toxicity, and insufficient targeting. Polymeric nanocarriers are currently employed as sophisticated tools in the field of oncology, offering the possibility to augment the administration and efficacy of anticancer therapies. In order to effectively eradicate prostate cancer, this review delves into the function of polymeric nanocarriers. Databases such as PubMed, ScienceDirect, and Google Scholar were utilized to do a comprehensive literature assessment. For this search, we used terms like "polymeric nanocarriers," "prostate cancer," "drug delivery," and "nanotechnology." Studies have shown that polymeric nanocarriers greatly improve the delivery and effectiveness of treatments for prostate cancer. Nanocarriers enhance the solubility, stability, and bioavailability of drugs, resulting in improved therapeutic effects. Functionalization using targeting ligands, such as folic acid and prostate-specific membrane antigen (PSMA) antibodies, has demonstrated the ability to enhance targeted specificity, resulting in a decrease in off-target effects and systemic toxicity. Polymeric nanocarriers facilitate precise and prolonged drug delivery, leading to elevated drug levels in tumor tissues. Polymeric nanocarriers are a notable breakthrough in the management of prostate cancer, providing precise medication administration, decreased toxicity, and improved therapy effectiveness. However, additional study is necessary to enhance the design of nanocarriers, evaluate their long-term safety, and enable their use in clinical applications. Continued interdisciplinary research and collaboration are essential for addressing current obstacles and maximizing the promise of polymeric nanocarriers in the treatment of prostate cancer.

Formulation and evaluation of gastroretentive drug delivery system

Gastroretentive Drug Delivery Systems (GRDDS) are advanced oral drug delivery technologies designed to extend the residence time of a drug in the stomach, improving the bioavailability and therapeutic efficacy of drugs absorbed in the upper gastrointestinal tract or exhibiting localized gastric activity. These systems are especially beneficial for drugs with a narrow absorption window or poor intestinal solubility. GRDDS utilize mechanisms such as floating systems that stay buoyant on gastric fluids, bioadhesive systems that adhere to the stomach lining, swelling systems that expand to prevent premature gastric emptying, and multiparticulate systems offering flexibility in dosage and controlled release. The formulation of GRDDS involves selecting biocompatible polymers and excipients that withstand the acidic gastric environment while releasing the drug in a controlled and sustained manner. These systems can reduce dosing frequency, enhance patient compliance, and provide consistent plasma drug levels, minimizing side effects. GRDDS are particularly valuable in treating chronic diseases such as diabetes, hypertension, gastrointestinal infections, and peptic ulcers. By leveraging innovative designs, GRDDS significantly advance therapeutic outcomes in modern pharmacotherapy.

Microfluidic-Assisted Silk Nanoparticles Co-Loaded with Epirubicin and Copper Sulphide: A Synergistic Photothermal–Photodynamic Chemotherapy Against Breast Cancer

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has emerged as a promising non-invasive cancer treatment, addressing issues like drug resistance and systemic toxicity common in conventional breast cancer therapies. Recent research has shown that copper sulphide (CuS) nanoparticles and polydopamine (PDA) exhibit exceptional photothermal conversion efficiency under 808 nm near-infrared (NIR) laser irradiation, making them valuable for cancer phototherapy. However, the effectiveness of PDT is limited in hypoxic tumour environments, which are common in many breast cancer types, due to its reliance on local oxygen levels. Moreover, single-modality approaches, including phototherapy, often prove insufficient for complete tumour elimination, despite their therapeutic strength. In this paper, a microfluidic-assisted approach was used to create multifunctional silk-based nanoparticles (SFNPs) encapsulating the chemotherapeutic drug Epirubicin (EPI), the PTT/PDT agent CuS, and the heat-activated, oxygen-independent alkyl radical generator AIPH for combined chemotherapy, PTT, and PDT, with a polydopamine (PDA) coating for enhanced photothermal effects and surface-bound folic acid (FA) for targeted delivery in breast cancer treatment. The synthesised CuS-EPI-AIPH@SF-PDA-FA nanoparticles achieved a controlled size of 378 nm, strong NIR absorption, and high photothermal conversion efficiency. Under 808 nm NIR irradiation, these nanoparticles selectively triggered the release of alkyl radicals and EPI, improving intracellular drug levels and effectively killing various breast cancer cell lines while demonstrating low toxicity to non-cancerous cells. We demonstrate that novel core–shell CuS-EPI-AIPH@SF-PDA-FA NPs have been successfully designed as a multifunctional nanoplatform integrating PTT, PDT, and chemotherapy for targeted, synergistic breast cancer treatment.

P-1213. Optimizing the synergy between Aztreonam & Avibactam for NDM plus OXA48 producing Carbapenem resistant Klebsiella pneumoniae infections: an innovative infusion method

Abstract Background Ceftazidime-avibactam (CAZ AVI) along with aztreonam (ATM) is used off-label for NDM+OXA48 producing carbapenem resistant Klebsiella pneumoniae (CR Kp). If the level of AVI is maintained at 2.5 μg/ml, it protects ATM from OXA48 & allows it to act against such CR Kp. In such a situation the MIC to ATM has been found in a published report to be 2 μg/ml. Table shows the measured protein bound drug levels. Estimated free drug levels are shown in brackets. Methods We used CAZ AVI (CAZ 2 grams and AVI 0.5 gram) infusion over 3 hours & ATM 2 grams infusion over the 2nd half an hour as shown in figure 1, in 5 patients infected with NDM+OXA48 CR Kp, as a proof-of-concept PK study. The rationale of starting the ATM infusion after the CAZ AVI infusion is begun is to allow AVI levels to build up & prevent inactivation of ATM by ESBL & OXA48. The administration of ATM over half an hour, rather than by a more prolonged infusion, may ensure a relatively high initial level of ATM, which is expected to remain for a considerable time owing to its long half life. Infusion strategy for Ceftazidime-Avibactam (CAZ-AVI) & Aztreonam (ATM) Results After measurement of protein bound levels, free AVI (fAVI) & free ATM (fATM) levels were estimated from the known extent of protein binding. As shown in table 1, all levels of estimated fAVI were above 2.5 mcg/ml. The estimated levels of fATM, at 5 hours after beginning the infusion were at or above 15.6 mcg/ml, with a mean of 45.6 mcg/ml & range of 15.6 to 98.2 mcg/ml. Hence time above 4 times the assumed ATM MIC of 2 mcg/ml, for more than 50% of the dosing interval was easily achieved in all the patients. Conclusion Thus, the PK/PD index obtained is higher than that needed for optimal killing & can suppress resistance which may be useful from the perspective of antimicrobial stewardship. Disclosures Rajeev Soman, MBBS, MD (General Medicine), FIDSA, Astellas: Honoraria|Biomeriux: Honoraria|Cipla: Honoraria|Emcure: Honoraria|Gilead: Honoraria|Glenmark: Honoraria|Gufic: Honoraria|Intas: Honoraria|MSD: Honoraria|Mylan: Honoraria|Pfizer: Honoraria Saiprasad Patil, Global Medical Affairs, Glenmark Pharmaceuticals Limited: Employee Amullya Pednekar, Global Medical Affairs, Glenmark Pharmaceuticals Limited: Employee Hanmant Barkate, Global Medical Affairs, Glenmark Pharmaceuticals Limited: Employee

P-967. Impact of simulated ID rounds for third year pharmacy students (P3s) in an infectious diseases (ID) elective

Abstract Background ID Rounds simulate real-world multidisciplinary ID rounds for P3s enrolled in the ID elective. Two faculty play the ID attending and 4th year pharmacy students on their Advanced Pharmacy Practice Experiences play the roles of the ICU fellow, nurse, microbiologist, and radiologist. An ID consult for a patient with post-influenza pneumonia along with the patient’s general information and basic labs are presented. P3s are guided to navigate the patient care process, collecting and assessing information, and formulating, implementing, and evaluating therapeutic recommendations. Challenges incorporated include a weight discrepancy, altering antimicrobials, monitoring drug levels, following cultures, and discharge planning. The purpose of this study was to assess the impact of ID Rounds on achieving Doctor of Pharmacy educational outcomes and professional activities. Methods An anonymous, electronic survey was distributed to P3s to assess the impact of ID Rounds. Survey questions were designed in accordance with the standards set by the American Association of Colleges of Pharmacy Curriculum Outcomes and Entrustable Professional Activities, using a Likert scale. Student perceptions were also collected. Results 36 P3s responded and all strongly agreed or agreed that ID Rounds helped them learn foundational knowledge of inpatient rounds and enhanced their professional skills by building and maintaining trust among their colleagues. Majority strongly agreed or agreed that ID Rounds helped them understand the role of a pharmacist in optimizing antimicrobial use (94.5%, 34/26), become better communicators (94.5%, 34/36), and support the achievement of shared goals on a team (97.2%, 35/26). Majority rated ID Rounds a 4 out of 5 in difficulty, found the activity as an engaging way of learning about inpatient rounds, and enjoyed participating. Conclusion ID Rounds allowed pharmacy students to achieve key standards in Doctor of Pharmacy educational outcomes and professional activities. Students responded positively to ID Rounds, which actively involved them in a real-world scenario, enabling the application of critical skills such as collaborative practice, critical thinking, and effective communication. These competencies are fundamental to the practice of pharmacy. Disclosures All Authors: No reported disclosures

P-1604. Utilization of MRSA Nasal PCR to De-escalate Vancomycin Therapy in Inpatients with Suspected Pneumonia

Abstract Background MRSA nasal screening has been proposed as a tool to facilitate de-escalation of vancomycin in patients with pneumonia. The objective of this study was to evaluate the impact of MRSA nasal PCR testing in patients with pneumonia in terms of length of anti-MRSA therapy and clinical outcomes. Methods This was a retrospective single center pilot study conducted at Mount Sinai Beth Israel during January 1, 2022 – March 31, 2022 (pre-availability of MRSA nasal PCR) and August 1, 2023 – October 31, 2023 (post-availability of MRSA nasal PCR). The primary outcome was the duration of vancomycin therapy in days in the pre-PCR compared to the post-PCR group. Secondary outcomes included the number of vancomycin levels drawn, 30- and 90- day mortality, hospital length of stay, and incidence of new acute kidney injury (AKI) during treatment. Comparisons were performed using Chi-squared or Fischer’s exact test for categorical variables and Student’s t test or the Mann-Whitney U test for continuous variables, as appropriate. P < .05 was considered statistically significant. Results One-hundred and eighty-five patients were included, 91 in the pre-PCR group and 94 in the post-PCR group. The most common pneumonia indication was community acquired pneumonia (CAP) in 78% of patients. Among patients that received vancomycin therapy for CAP, only 30% (21/70) and 17.3% (13/75) had risk factors warranting anti-MRSA therapy in the pre-PCR and post-PCR groups respectively. The median duration of vancomycin therapy was significantly shorter in the post-PCR group than the pre-PCR group (0.9 days vs. 1.8 days; p < .05). Fewer patients required 2 or more vancomycin levels drawn in the post-PCR versus the pre-PCR group (20.2% vs 41.8%; p < .05). 30-day mortality was lower in the post-PCR group (12.8% vs 25.3%), but not significantly (p=0.08). No differences were found in other clinical outcomes including 90- day mortality, hospital length of stay, and incidence of new AKI during treatment. Conclusion MRSA nasal PCR testing resulted in shorter duration of vancomycin therapy and reduced drug level monitoring without compromising clinical outcomes in patients with suspected pneumonia. Additional education is needed to ensure appropriate utilization of empiric anti-MRSA therapy in CAP patients with risk factors. Disclosures All Authors: No reported disclosures

P-1240. Optimal Vancomycin Model Selection for Obese Patients Receiving Outpatient Parenteral Antimicrobial Therapy (OPAT)

Abstract Background Optimal OPAT dosing of vancomycin (VAN) is challenging in obese patients. Multiple Bayesian pharmacokinetics (PK) models to aid in AUC estimation exist, including several obesity-specific models. PK population models in the absence of drug serum levels (a priori) are useful to initiate therapy, but once drug serum levels are obtained, model performance is based upon individual patient PK (a posteriori). This study is the first evaluation of the optimal PK model for obese patients receiving OPAT. Methods Analysis included all OPAT patients who received VAN in 2022-2023 with at least one therapeutic drug level, and a body mass index (BMI) ≥ 30 kg/m2. Data collection included demographics, anthropometrics, treatment information, laboratory values, and AUC24. Ten PK models were used to predict VAN serum concentrations and calculate AUC24 using a Bayesian dosing software. The performance of each model was assessed using a priori root mean square error (RMSE) and a posteriori RMSE for each model. The average RMSE was also calculated for patients with BMI 30-39.9 kg/m2 and for those ≥40 kg/m2. The model with the best performance for each BMI category was reported. Results Of 920 VAN OPAT patients, 420 (45.6%) were identified with a BMI ≥30 kg/m2. Population characteristics are included in Table 1, with 80% having a BMI 30-39.9 kg/m2. Median duration of VAN was 23 days (IQR: 12-35). The RMSE calculations per model and BMI groups are shown in Table 2. Best model fit varied among BMI groups and is indicated in bold type. For RMSE a priori, the Crass model performed the best for BMI 30-39.9 kg/m2 and the UVM model was best for BMI ≥40 kg/m2. The RMSE a posteriori with best performance for BMI 30-39.9 kg/m2 was Thompson capped, with UVM and Goti also performing well. For BMI ≥40 kg/m2, RMSE a posteriori, the Goti model was the best performing. Conclusion Obesity models provided good performance for a priori predictions and performed similarly to non-obese models in a posteriori predictions. This research supports use of both obesity and non-obesity models for VAN PK in OPAT. Disclosures Joseph F. John, Jr., MD, FACP, FIDSA, MicroGenDx: Advisor/Consultant Lucinda J. Van Anglen, PharmD, Cumberland Pharmaceuticals: Grant/Research Support|Ferring Pharmaceuticals: Grant/Research Support|Novartis Pharmaceuticals: Grant/Research Support|Takeda Pharmaceuticals: Grant/Research Support

P-1152. Cefepime, Meropenem, and Piperacillin Therapeutic Drug Monitoring in Neonatal and Pediatric Patients

Abstract Background Pharmacokinetics of beta-lactams vary widely in neonatal and pediatric patients due to developmental biology and critical illness. Cefepime (FEP), meropenem (MEM), and piperacillin/tazobactam (TZP) are highly susceptible to pharmacokinetic changes as hydrophilic, small molecules with renal clearance. Subtherapeutic levels are associated with clinical and microbiologic failure, and supratherapeutic levels associated with toxicity. Beta-lactam therapeutic drug monitoring (TDM) may optimize the effectiveness and safety of these agents. The purpose of this investigation is to describe the % of pediatric and neonatal patients with beta-lactam serum levels within target range. Methods In August 2023, TDM launched at the Mayo Clinic Children’s Center for select patients treated with FEP, MEM, or TZP with expected durations ≥ 48 hours, or who were on kidney replacement therapy (KRT), extracorporeal membrane oxygenation (ECMO), weighed > 120 kg, had a BMI > 95th percentile, or at the discretion of pediatric ID team. Validated drug assays were performed daily, Monday through Friday. A two-level sampling strategy was preferred with a peak 1 hour after the end of the infusion and a trough 30 minutes before the next dose. Empiric trough target ranges were set at FEP 8-50 mg/L, MEM 2-30 mg/L, and piperacillin 16-150 mg/L. These target ranges were adjusted with confirmed microbiology to a time above the minimum inhibitory concentration of the organism for 100% of the dosing interval (100%T > MIC). Results From August 2023 to April 2024, 74 episodes of TDM were performed on 45 patients. Thirty-seven (82%) patients were in an intensive care unit (ICU) at the time of TDM, 8/45 (22%) of whom were in the neonatal ICU. Target range was achieved in 67% of patients on FEP, 50% on MEM, and 52% on TZP. Median (IQR) trough values were 22.1 (8.6, 44.2) mg/L for FEP, 0.6 (0, 4.1) mg/L for MEM, and 15.5 (3.8, 27.1) mg/L for TZP. Seven levels were above target for FEP and 0 for MEM and TZP. Seven levels were below target for FEP, 4 for MEM, and 11 for TZP. Conclusion Implementation of a TDM program for FEP, MEM and TZP in pediatric and neonatal patients revealed drug levels frequently outside target range. TDM may facilitate dose individualization to optimize medication efficacy and minimize toxicity. Disclosures Raymond Stetson, MD, MS, Moderna: Grant/Research Support Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member Erin F. Barreto, PharmD, MSc, Baxter Health: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant

P-1046. Isavuconazonium Utilization in Pediatric Patients at a Free-Standing Children’s Hospital

Abstract Background Isavuconazonium sulfate is a newer triazole antifungal used for the treatment of invasive aspergillosis and mucormycosis. In December 2023, the FDA expanded approval for isavuconazonium sulfate (Cresemba) to include pediatric patients 1 year and older. The most common adverse effect requiring monitoring is hepatotoxicity. Routine therapeutic drug monitoring is not recommended for most patients but may be considered if there is a concern for toxicity, therapeutic failure, or impaired drug absorption. With limited published data in pediatric patients, our aim is to evaluate the use of isavuconazonium at Children's Hospital Los Angeles (CHLA) and assess safety and tolerability in our patient population. Methods A retrospective chart review was performed to evaluate utilization of isavuconazonium from 01/01/2023 – 12/31/2023 at CHLA. Demographic data, Infectious Diseases consultation, indication for therapy, liver function before and during treatment, and serum drug level results were collected and analyzed. Results A total of 54 patient encounters included an isavuconazonium order during the review period. All study patients had a primary diagnosis of leukemia or stem cell transplant (SCT), the most common (45%) being Acute Lymphoblastic Leukemia (ALL). 3 patients had mildly elevated liver function tests (LFTs) at baseline, and 6 total patients developed grade 3 or 4 liver toxicity during therapy. The most common indication for treatment was empiric or definitive treatment of invasive fungal infection, with 15 (28%) and 20 (37%) patients, respectively. 19 patients (35%) received off-label prophylaxis for invasive fungal infection due to contraindications to alternative antifungal agents. 33 of 54 patients had at least one serum trough level measured at steady state. Although a therapeutic target range is not well established, 26 patients (79%) achieved levels within typical expected range of 1-5 mg/L. Of 3 patients with trough level < 1 mg/L, 2 were determined to be due to non-adherent to outpatient therapy. Conclusion Based on serum drug levels and LFT results collected for routine therapeutic monitoring, isavuconazonium appears well-tolerated for treatment or prophylaxis of invasive fungal infection in our immunocompromised pediatric population. Disclosures All Authors: No reported disclosures

Therapeutic drug monitoring and neutralizing anti-drug antibody detection to optimize TNF-alpha inhibitor treatment for uveitis

BackgroundAdalimumab taken every other week is an effective treatment in patients with chronic refractory uveitis. Patients who have a suboptimal response to this treatment may suffer from recurrent inflammation and vision loss. Here, we investigated the use of therapeutic drug monitoring and neutralizing anti-drug antibody detection as a strategy to optimize tumor necrosis factor (TNF)-alpha inhibitor treatment in patients who have a suboptimal response to the initial dosing of adalimumab.MethodRetrospective cohort study performed in two tertiary referral uveitis services in the United States between 2015 to 2023. Patients with non-infectious uveitis who had a suboptimal response to every two-week dosing of adalimumab and underwent serum adalimumab level with reflex to anti-drug antibody testing were followed. Patients were considered to have neutralizing drug antibodies when serum drug levels were low (less than or equal to 6 mcg/mL) and anti-adalimumab antibodies were present on reflex testing. Treatment adjustment was made by clinicians with the knowledge of serum adalimumab level and the presence or absence of neutralizing drug antibodies. Every two-week dosing of adalimumab was either escalated to weekly dosing or switched to infliximab, an alternate TNF-alpha inhibitor, based on these findings. The primary outcome was success or failure at 12 months, as determined by disease inactivity on steroid-sparing therapy.Results32 patients with suboptimal response to the initial dosing of adalimumab were included. 31.2% (n=10) of patients were found to have neutralizing drug antibodies. All patients with neutralizing drug antibodies underwent a medication switch to infliximab with a remission rate of 40% at 12 months. Patients without neutralizing drug antibodies (n=22) underwent dose escalation (77.3%; n=17) or medication switch (22.7%; n=5) and achieved a remission rate of 68.2% at 12 months. Altogether, treatment adjustment based on therapeutic drug monitoring and neutralizing drug antibody detection, in our cohort, resulted in a remission rate of 62.5%.ConclusionsFor patients with uveitis experiencing suboptimal therapeutic response to adalimumab dosed every two weeks, therapeutic drug monitoring and neutralizing drug antibody detection may help clinicians optimize TNF-alpha inhibitor treatment.

Determination of The Level of Paracetamol and Tramadol Hcl Mixture in Tablets by Chemometric Method by Fourier Transform Infrared Spectrophotometry

Fixed-dose combinations of paracetamol and tramadol HCl are effective in the treatment of moderate to severe pain. Therefore, the determination of the levels of the mixture of paracetamol and tramadol HCl is very important for the pharmaceutical industry. The purpose of this study was to determine the levels of paracetamol and tramadol HCl mixture using Fourier Transform Infrared combined with partial least square (PLS) chemometric method. This study was conducted by making a calibration model and chemometric validation of each of the five concentrations measured absorbance at specific wave numbers of paracetamol and tramadol HCl. The results of the study on PLS multivariate calibration of paracetamol and tramadol HCl with RMSECV values of 0.06279 and 0.03785, PRESS values of 0.02366 and 0.00860, and R2 values of 0.9995 0.9998, respectively. All validation parameters are within the acceptable range. This indicates that the method can be used to accurately determine drug levels without separation

Comparative Analysis of 2 Commercially Available Assays for Therapeutic Drug Monitoring of Infliximab and Adalimumab.

Tumor necrosis factor is a crucial proinflammatory cytokine in immune-mediated diseases. Tumor necrosis factor inhibitors (TNFi), such as infliximab and adalimumab, effectively treat rheumatological and digestive disorders. However, challenges such as primary nonresponse, secondary treatment failure, or adverse reactions limit their efficacy. Monitoring TNFi levels is essential for optimizing treatment and improving outcomes. An enzyme-linked immunosorbent assay (ELISA; Promonitor) was compared with 2 commercially available methods for quantifying infliximab and adalimumab levels: the chemiluminescence assay (i-Track10) and fluorescence assay (Afias-10). Serum samples from 166 patients with inflammatory bowel disease were analyzed. Drug levels were measured using i-Track10, Afias-10, and Promonitor. Spearman's correlation analysis, Bland-Altman analysis, analysis of differences, Passing-Bablok regression, and Cohen kappa for agreement assessment were used for statistical analysis. Strong correlations were observed between Promonitor and Afias-10 for infliximab (rs = 0.982) and adalimumab (rs = 0.972), and with i-Track10 (rs = 0.935 for infliximab, rs = 0.947 for adalimumab). However, significant differences indicated noninterchangeability with ELISA. Passing-Bablok regression showed systematic and proportional biases. Cohen kappa exhibited higher concordance with Afias-10 for therapeutic ranges (κ = 0.962 for infliximab, κ = 0.849 for adalimumab) compared with i-Track10. Afias-10 and i-Track10 are suitable for TNFi monitoring but are not interchangeable with ELISA. Consistent assay methods should be used for patient monitoring to ensure accuracy and reliability.

Prevalence and clinical implications of anti-drug antibody formation and serum drug levels among patients with IBD receiving anti-TNF therapy: A cross-sectional study.

The emergence of tumor necrosis factor inhibitors (anti-TNF) has considerably changed the management of inflammatory bowel disease (IBD) in patients who do not respond to traditional therapies. This study assesses the prevalence of anti-TNF drug levels (DLs) and antibodies (ATAbs) in patients with IBD in Saudi Arabia and explores their associations with IBD type and prior anti-TNF failure. This cross-sectional study included patients aged 14-75 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), treated with anti-TNF medications at King Fahad Medical City over January 2016 to December 2022. Data were analyzed using descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson's Chi-squared test, and multinomial logistic regression. Among 392 patients with IBD (median age, 31 years), 75.8% were diagnosed with CD and 24.2% with UC. Anti-TNF levels were subtherapeutic in 27.0% patients, therapeutic in 21.5%, and supratherapeutic in 51.5%. ATAbs were negative in 73.1% patients, weakly positive in 9.8%, and positive in 17.1%. Subtherapeutic anti-TNF levels were significantly associated with positive ATAbs (P < 0.001). Prior anti-TNF therapy failure was observed in 37.2% cases, with 15.3% showing immunogenicity. No significant demographic differences were noted across ATAbs groups. We highlight the prevalence of subtherapeutic and supratherapeutic anti-TNF levels among patients with IBD in Saudi Arabia and their association with ATAbs. The findings underscore the importance of monitoring anti-TNF DLs and ATAbs to optimize treatment outcomes in IBD management. Future research should focus on the longitudinal impact of these factors and explore genetic predictors of treatment response.

Computational Evaluation of Improved HIPEC Drug Delivery Kinetics via Bevacizumab-Induced Vascular Normalization

Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy.

P0679 Therapeutic Drug Monitoring of the Infliximab (anti-TNF) Level with Bedside Kit in Inflammatory Bowel Disease

Abstract Background Approximately half (10-40%) of the Inflammatory Bowel Disease (IBD) patients using Infliximab (IFX) develop secondary loss of response due to drug levels falling below the therapeutic range. This study aims to identify drug levels, influencing factors and parameters that may be useful in predicting target drug levels. Methods The pre-infusion drug levels and associated laboratory parameters were evaluated in IBD patients on maintenance dose of IFX (5-15 mg/kg every 4-8 weeks) between Nov2021 - Oct2024. Drug levels were measured using a bedside kit capable of quantitatively detecting values between 0.4-20 µg/ml. Results In total, 931 single pre-infusion measurements from 415 different patients, and dual measurements at weeks 4 and 8 from 116 patients were separately evaluated. 82% of the patients in the single measurement group, and 84% in the double measurement group had Crohn’s disease(CD), rest having Ulcerative Colitis. The most used doses in the single measurement group were 5 mg/8 weeks and 10 mg/4 weeks (Table 1). In the single measurement group, median albumin was 4.4 (IQR: 0.5), and median CRP was 3.1 (IQR: 6.4). Drug levels were below 5 µg/ml in 33% of measurements. CRP showed a significant difference according to drug level groups (Table 2), while no such difference was observed for albumin. In the measurable IFX range (0.4-20 µg/ml), correlation analysis revealed a weak negative correlation between CRP and drug levels (r: -0.09, p: 0.03). Regression analysis showed that lower CRP, higher drug dose, and CD diagnosis were independently associated with achieving &amp;gt;5 µg/ml drug levels. In the dual measurement group: The median CRP levels of patients at weeks 4 and 8 were 2.1 (5.1) and 2.6 (6.2), respectively (p&amp;gt;0.05). Among patients with IFX levels &amp;gt;20 µg/ml at week 4, 79% maintained levels &amp;gt;5 µg/ml at week 8, while this rate dropped to 71% for those with levels &amp;gt;10 µg/ml. Only 67% of patients with levels &amp;gt;5 µg/ml at week 4 maintained a level of &amp;gt;5 µg/ml at week 8 (all p-values &amp;lt;0.001). Conclusion As drug levels increase, significant reductions in CRP levels are observed. Therefore, low CRP levels may predict the likelihood of achieving the therapeutic range. Dose adjustment should be considered in cases with high CRP levels. Achieving a high drug level (&amp;gt;20 µg/ml) at 4th week is an important indicator of achieving at least an acceptable drug level (&amp;gt;5 µg/ml) at the end of treatment. (8th week).

P1011 Correlations of clinical characteristics and serum proteins with drug levels: A multicentre cohort study of patients with inflammatory bowel disease starting biologics

Abstract Background Inter-individual differences in drug clearance are common in inflammatory bowel disease (IBD) patients treated with biologics. Associations between inflammatory markers, clinical features, and drug levels may indicate that the inflammatory immune response influences the pharmacokinetics of biologics. We assessed the impact of inflammatory and immunity-related proteins on drug levels in IBD. Methods Serum samples from 144 IBD patients initiating biologics in a prospective multicentre cohort were analysed using AFIAS-3 (Boditech Med Inc. Korea). The primary outcome was drug levels after the end of induction treatment (post-induction), analysed as continuous variables or categorised into high or low groups based on the median. Correlations were assessed using the Pearson’s correlation coefficients with false discovery rate (FDR) adjustment. Predictive capacity of clinical and protein data was evaluated with regularised linear regression models. Analyses were stratified by treatment (infliximab, adalimumab, vedolizumab) and diagnosis (Crohn’s disease (CD), ulcerative colitis (UC)). Results Patient demographics and clinical characteristics are provided in Table 1. Median (interquartile range, IQR) post-induction infliximab levels were 5.3 (2.2-9.5) µg/ml in patients with CD (n=34) and 3.8 (1.7-5.6) µg/ml in UC (n=33). The corresponding levels were 12.5 (7.0-16.1) µg/ml (n=36) and 8.8 (5.7-12.7) µg/ml (n=13) for adalimumab, 13.9 (6.4-24.4) µg/ml (n=19) and 17.7 (9.8-22.6) µg/ml (n=9) for vedolizumab. Principal component analyses revealed potential baseline protein profile differences between patients with high vs low post-induction levels for infliximab (p=0.09) and adalimumab (p=0.07) in CD, but no differences for vedolizumab (p=0.78) or UC. Individual protein analyses indicated that patients with higher drug levels post-induction seemed to display lower baseline estimates of inflammatory proteins compared to those with lower drug levels. However, statistical significance after correction for multiple comparisons was only observed for CDCP1 in adalimumab-treated CD patients (PFDR=0.04) (Figure 1). Additionally, baseline Flt31 (r=-0.57, PFDR=0.03) and Wisp1 (r=-0.61, PFDR=0.02) correlated with post-induction s-adalimumab levels in CD, while Mcp3 (r=-0.89, PFDR=0.04) and Frgamma (r=-0.87, PFDR=0.05) correlated in UC. Integrating baseline protein data in prediction models for post-induction drug levels did not improve their accuracy compared to models based on only clinical and biochemical variables. Conclusion Inflammatory protein levels may influence post-induction drug levels in IBD, particularly in adalimumab treated CD patients. This insight could aid in optimising personalised treatment.