Intravenous Dosing Regimens Research Articles

A Randomized, Blinded, Vehicle-Controlled Dose-Ranging Study to Evaluate and Characterize Remdesivir Efficacy Against Ebola Virus in Rhesus Macaques

Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure. Thirty rhesus macaques underwent surgical implantation of telemetry devices for the fine-scale monitoring of body temperature and activity, as well as central venous catheters, to enable treatment administration and blood collection. Treatment, consisting of a loading dose of RDV followed by once-daily maintenance doses for 11 days, was initiated 4 days after virus exposure when all animals were exhibiting disease signs consistent with incipient EBOV disease as well as quantifiable levels of EBOV RNA in plasma. In the RDV treatment groups receiving loading/maintenance doses of 5/2.5 mg/kg, 10/5 mg/kg, and 20/10 mg/kg, a total of 6 of 8 (75%), 7 of 8 (87.5%), and 5 of 7 (71.4%) animals survived, respectively. In the vehicle control group, one of seven animals (14.3%) survived. The improved survival rate compared to the control group was statistically significant only for the 10/5 mg/kg RDV treatment group. This treatment regimen also resulted in a significantly lower systemic viral load compared to the vehicle control after a single RDV treatment. All three RDV regimens produced a significantly lower systemic viral load after two treatments. For most animals, RDV treatment, regardless of dose, resulted in the amelioration of many of the clinical–pathological changes associated with EBOV disease in this model.

Integrating real-world data and machine learning: A framework to assess covariate importance in real-world use of alternative intravenous dosing regimens for atezolizumab.

The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision-recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.

Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework Integrating In Vitro and Clinical Insights.

Voriconazole (VRC), a broad-spectrum antifungal drug, exhibits nonlinear pharmacokinetics (PK) due to saturable metabolic processes, autoinhibition and metabolite-mediated inhibition on their own formation. VRC PK is also characterised by high inter- and intraindividual variability, primarily associated with cytochrome P450 (CYP)2C19 genetic polymorphism. Additionally, recent in vitro findings indicate that VRC main metabolites, voriconazole N-oxide (NO) and hydroxyvoriconazole (OHVRC), inhibit CYP enzymes responsible for VRC metabolism, adding to its PK variability. This variability poses a significant risk of therapeutic failure or adverse events, which are major challenges in VRC therapy. Understanding the underlying processes and sources of these variabilities is essentialfor safe and effective therapy. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) modelling framework that elucidates the complex metabolism of VRC and the impact of its metabolites, NO and OHVRC, on the PK of the parent, leveraging both in vitro and in vivo clinical data in a middle-out approach. A coupled parent-metabolite PBPK model for VRC, NO and OHVRC was developed in a stepwise manner using PK-Sim® and MoBi®. Based on available in vitro data, NO formation was assumed to be mediated by CYP2C19, CYP3A4, and CYP2C9, while OHVRC formation was attributed solely to CYP3A4. Both metabolites were assumed to be excreted via renal clearance, with hepatic elimination also considered for NO. Inhibition functions were implemented to describe the complex interaction network of VRC autoinhibition and metabolite-mediated inhibition on each CYP enzyme. Using a combined bottom-up and middle-out approach, incorporating data from multiple clinical studies and existing literature, the model accurately predicted plasma concentration-time profiles across various intravenous dosing regimens in healthy adults, of different CYP2C19 genotype-predicted phenotypes. All (100%) of the predicted area under the concentration-time curve (AUC) and 94% of maximum concentration (Cmax) values of VRC met the 1.25-fold acceptance criterion, with overall absolute average fold errors of 1.12 and 1.14, respectively. Furthermore, all predicted AUC and Cmax values of NO and OHVRC met the twofold acceptance criterion. This comprehensive parent-metabolite PBPK model of VRC quantitatively elucidated the complex metabolism of the drug and emphasised the substantial impact of the primary metabolites on VRC PK. The comprehensive approachcombining bottom-up and middle-out modelling, therebyaccounting for VRC autoinhibition, metabolite-mediated inhibition, and the impact of CYP2C19 genetic polymorphisms, enhances our understanding of VRC PK. Moreover, the model can be pivotal in designing further in vitro experiments, ultimately allowing for extrapolation to paediatric populations, enhance treatment individualisation and improve clinical outcomes.

Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis.

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m2, without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC.

High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma

BackgroundCemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are...

Immunogenicity of Cemiplimab: Low Incidence of Antidrug Antibodies and Cut-Point Suitability Across Tumor Types.

The immunogenicity of cemiplimab, a fully human immunoglobulin G4 monoclonal antibody directed against programmed cell death1, was assessed in patients across multiple tumor types. The development of antidrug antibodies (ADAs) against cemiplimab was monitored using a validated bridging immunoassay. To identify ADA-positive samples in the assay, statistically determined cut points were established by analyzing baseline clinical study samples from a mixed population of different tumor types, and this validation cut point was used to assess immunogenicity in all subsequent studies. Regulatory guidance requires that ADA assay cut points be verified for appropriateness in different patient populations. Thus, for the cemiplimab ADA assay, we evaluated whether each new oncology population was comparable with the validation population used to set the cut point. Assay responses from 2393 individual serum samples from 8 different tumor types were compared with the validation population, using established statistical methods for cut-point determination and comparison, with no significant differences observed. Across tumor types, the immunogenicity of cemiplimab was low, with an overall treatment-emergent ADA incidence rate of 1.9% and 2.5% at intravenous dose regimens of 3mg/kg every 2weeks and 350mg every 3weeks, respectively. Moreover, no neutralizing antibodies to cemiplimab were detected in patients with ADA-positive samples, and there was no observed impact of cemiplimab ADAs on pharmacokinetics. Study-specific cut points may be required in some diseases, such as immune and inflammatory diseases; however, based on this analysis, in-study cut points are not required for each new oncology disease indication for cemiplimab.

A Comparison of Dobutamine, Norepinephrine, Vasopressin, and Hetastarch for the Treatment of Isoflurane-Induced Hypotension in Healthy, Normovolemic Dogs.

Isoflurane is a commonly used inhalation anesthetic in species undergoing veterinary care that induces hypotension, impacting organ perfusion, making it imperative to minimize its occurrence or identify effective strategies for treating it. This study evaluated and compared the hemodynamic effects of DOB, NEP, VAS, and HES in twelve isoflurane-anesthetized Beagle dogs. The order of the first three treatments was randomized. HES was administered last. Data were collected before treatments (baseline) and after 10 min of a sustained MAP of <45 mmHg induced by a high end-tidal isoflurane concentration (T0). Once treatment was initiated and the target MAP was achieved (65 to 80 mmHg) or the maximum dose reached, data were collected after 15 min of stabilization (T1) and 15 min after (T2). A 15 min washout period with a MAP of ≥65 mmHg was allowed between treatments. The intravenous dosage regimens started and were increased by 50% every five minutes until the target MAP or maximum dose was reached. The dosages were as follows: DOB, 5-15 μg/kg/min; NEP, 0.1-2 μg/kg/min; VAS, 0.5-5 mU/kg/min; and HET, 6% 1-20 mL/kg/min. DOB improved CO, DO2, and VO2, but reduced SVR. VAS elevated SVR, but decreased CO, DO2, and VO2. HES minimally changed BP and mildly augmented CO, DO2, and VO2. These treatments failed to reach the target MAP. NEP increased the arterial BP, CO, MPAP, and PAWP, but reduced HR. Norepinephrine infusion at 0.44 ± 0.19 μg/kg/min was the most efficient therapy for correcting isoflurane-induced hypotension.

Remifentanil at a Relatively Elevated Dose in Active Phase is Safe and More Suitable Than Fixed Lower Dose for Intravenous Labor Analgesia.

Intravenous labor analgesia is recommended as an alternative for parturients who have contraindications to epidural analgesia. There are several opioid analgesics and different administering regimens used in the clinic. This study aimed to compare the effectiveness and safety of two intravenous remifentanil dosage regimens in the first labor stage. One hundred and fifteen parturients with a contraindication to epidural analgesia but were willing to receive systemic labor analgesia were randomized into group A received a fixed dose of remifentanil throughout the first stage of labor, and group B received an elevated dose of remifentanil during the active phase of the first stage both by patient-controlled analgesia (PCA). Maternal numerical rating scale (NRS) pain score and oxygen desaturation, sedation efficacy, satisfaction, as well as maternal and fetal adverse reactions were recorded and compared. The mean NRS pain scores before analgesia and in the latent phase showed no statistically significant difference between the two groups (P > 0.05). However, during the active phase, group B demonstrated significantly lower mean NRS pain scores and lowest pain score compared to group A (P < 0.05). Furthermore, group B exhibited higher overall sedation scores and satisfaction scores in comparison to group A (P < 0.05). The incidence of adverse reactions between the two groups was similar (P > 0.05). Relatively elevated intravenous dosage of remifentanil with PCA during the active phase in the first stage of labor is safe and more effective than a fixed-dosage regimen for labor analgesia. This study was registered with ChiCTR on 24/08/2021 with trial identification number: ChiCTR2100050247. First participant was recruited on 31/08/2021. The last patient was recruited on 12/08/2022.

#4033 RAPID COMPLEMENT INHIBITION WITH THE C5 INHIBITOR CROVALIMAB: A TIMING ANALYSIS USING ANIMAL MODEL AND COMPOSER TRIAL DATA

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS) is a life-threatening disease, characterised by acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia due to complement dysregulation. Currently approved treatments for aHUS include the anti-complement C5 monoclonal antibodies eculizumab and ravulizumab. Although currently approved therapeutic options are effective at both inhibiting complement-mediated thrombotic microangiopathy (TMA) and improving renal function, the regular intravenous (IV) infusion dosing regimens impose a significant treatment burden, particularly in paediatric patients (pts) with aHUS, who may need dialysis in the future due to chronic kidney injury and would benefit from preservation of vascular access. Crovalimab is a novel monoclonal antibody developed against complement C5, engineered to allow for small volume subcutaneous (SC) self-injection every 4 weeks, in a weight-based dosing regimen [1]. In the adaptive Phase I/II COMPOSER trial (NCT03157635) evaluating crovalimab in pts with paroxysmal nocturnal haemoglobinuria (PNH), that, like aHUS, is a complement disorder characterised by uncontrolled complement activation, crovalimab has shown maintained disease control and was well tolerated after a median exposure of 3 years. Further, a Phase III study evaluating crovalimab in previously untreated pts met its primary efficacy endpoints [2]. The efficacy and safety of crovalimab are currently being evaluated in adult and paediatric pts with aHUS, either treatment-naive or switching from another complement inhibitor, in the ongoing Phase III single-arm COMMUTE-a and COMMUTE-p trials [3]. Due to the rapidly progressing nature of aHUS, pts experiencing a TMA require rapid suppression of complement activation upon diagnosis to shut down the complement cascade and avoid further kidney deterioration and organ damage. Here, data from in vivo models and the COMPOSER trial were used to determine the time to complete complement inhibition after first crovalimab IV dose. Method Crovalimab's ability to suppress C5 function and complement activity rapidly was initially studied in in vivo models of cynomolgus monkeys. This study assessed the pharmacokinetics and pharmacodynamics of crovalimab in these monkeys after a single IV or SC dose. As part of this study, four animals per group were evaluated with single 4 mg/kg IV and 20 mg/kg IV doses. Crovalimab was also evaluated in the four-part, Phase I/II COMPOSER trial. Part 2 (n = 10) and Part 4A (n = 8) enrolled pts with PNH who were naive to complement inhibition. Pts in Part 2 received crovalimab 375 mg IV on Day 1, 500 mg IV on Day 8, 1000 mg IV on Day 22 and 170 mg SC weekly from Day 36 for 20 weeks. Pts in Part 4A received an optimised crovalimab dosing regimen of 1000 mg IV on Day 1, 340 mg SC on Days 2, 8, 15, and 22 and 680 mg SC Q4W from Day 29 onwards for 20 weeks. Crovalimab concentration, free C5 and complement activity were measured using validated assays in cynomolgus monkeys and in pts with PNH. Results Compared with baseline values in cynomolgus monkeys, a single crovalimab IV dose of 4 mg/kg reduced mean free C5 concentration by 99.6% and terminal complement activity by 81.4%, within 5 minutes after administration. In treatment-naive pts from COMPOSER Parts 2 and 4, mean free C5 concentration dropped to below 1 μg/mL, indicating a high level of target engagement within 1–6 hours from the first IV dose (Figure 1). Correspondingly, inhibition of terminal complement activity was reached within 1 hour, with values near or below the lower limit of quantification (10 U/mL; Figure 2). Complete complement blockade was generally maintained long-term, up to Week 20, in both Parts 2 and 4, regardless of dose. Conclusion Crovalimab induced a complete, rapid, and sustained blockade of terminal complement activity in both non-human primates and pts with PNH, within hours from first dose. The dosing schedule of crovalimab included an initial IV loading dose, allowing for a rapid onset of action, followed by a convenient long-term SC maintenance regimen.

Evaluation of THEO-260 as a novel oncolytic virus therapy for treating stromal rich tumours.

e14573 Background: Stromal rich tumours pose a significant challenge to the effectiveness of systemic anticancer therapies, including immunotherapies and oncolytic viruses. This is due to the abundance of cancer associated fibroblasts (CAFs) that suppress immune cells and limit drug penetration. THEO-260 is a potent, mechanistically novel oncolytic virus therapy intrinsically capable of lysing both cancer cells and CAFs, and is currently in development for late stage relapsed refractory ovarian cancer. Methods: The efficacy and safety of THEO-260 was assessed in multicellular spheroids, in patient-derived ex vivo fresh ovarian samples and in mouse models of human stromal tumours. Results: Unpassaged ascites and tumour samples collected from cytoreductive surgeries for advanced ovarian cancer (n=24 independent patients) were treated with a clinically-relevant dose of THEO-260. THEO-260 effectively killed the cancer cell (EpCAM+ EGFR+PDL1+ CA125+) and CAF (FAP+) populations, being efficacious in treatment-naive and platinum-resistant patient samples. Importantly, the T cell population in these patients, in addition to primary normal fibroblasts (including intestinal, pulmonary, dermal, cardiac, uterine fibroblasts) from healthy donors, were not damaged. Ex vivo studies show THEO-260 stimulates effector T cell responses upon tumour lysis as indicated by IFNγ release. Demonstrating suitability as an IV delivered agent, THEO-260 was active in pooled human serum and whole human blood (n = 10 donors). THEO-260 excels in low nutrient, low proliferative environments, typical of human solid tumours and has been developed with a view to persist in the tumour microenvironment without the need for repeated cycles of delivery. THEO-260 is well tolerated in vivo following a clinically relevant intravenous dosing regimen. In PARP inhibitor and platinum resistant ovarian cancer murine models containing human CAFs and cancer cells, THEO-260 shows antitumor efficacy, with a complete reduction in tumour volume in subcutaneous and intraperitoneal systems, and superiority to SOC. Virus activity is not restricted to ovarian cancer, with cell line data demonstrating killing in additional solid tumour types, including pancreatic, colorectal, lung, and breast cancer. THEO-260 exhibits genetic and temperature based stability, and GMP manufacturing to high yields is underway. Conclusions: Taken together, we present a preclinical data package for THEO-260 supporting progression to Phase I clinical trials.

Implementation of 2D barcode medication labels and smart pumps in pediatric acute care: Lessons learned.

In pediatric intensive care, prescription, administration, and interpretation of drug doses are weight-dependent. The use of standardized concentrations simplifies the preparation of drugs and increases safety. For safe administration as well as easy interpretation of intravenous drug dosing regimens with standardized concentrations, the display of weight-related dose rates on the infusion device is of pivotal significance. We report on challenges in the implementation of a new information technology-supported medication workflow. The workflow was introduced on eight beds in the pediatric heart surgery intensive care unit as well as in the pediatric anesthesia at the University of Bonn Medical Center. The proposed workflow utilizes medication labels generated from prescription data from the electronic health record. The generated labels include a 2D barcode to transfer data to the infusion devices. Methods Clinical and technical processes were agilely developed. The reliability of the system under real-life conditions was monitored. User satisfaction and potential for improvement were assessed. In addition, a structured survey among the nursing staff was carried out. The questionnaire addressed usability as well as the end-users' perception of effects on patient safety. The workflow has been applied 44111 times during the pilot phase. A total of 114 known failures in the technical infrastructure were observed. The survey showed good ratings for usability and safety (median "school grade" 2 or B for patient safety, intelligibility, patient identification and handling). The medical management of the involved acute care facilities rated the process as clearly beneficial regarding patient safety, suggesting a rollout to all pediatric intensive care areas. A medical information technology-supported medication workflow can increase user satisfaction and patient safety as perceived by the clinical end-users in pediatric acute care. The successful implementation benefits from an interdisciplinary team, active investigation of possible associated risks, and technical redundancy.

Tannic Acid Lipid Nanoparticles can Deliver Messenger RNA Payloads and Improve their Endosomal Escape

AbstractEven though lipid nanoparticles (LNPs) can deliver messenger RNA (mRNA) payloads into cells, their efficiency is often limited by endosomal trapping which prevents RNA payloads from acting therapeutically. Improving the percentage of RNA LNPs that can escape from endosomes and enter the cytoplasm is therefore an area of active research interest that could lead to improved safety profiles and reduced manufacturing costs of mRNA drugs. Here, tannic acid mRNA LNPs [TA(+) mRNA LNPs] are reported as an effective delivery platform for the delivery of mRNA payloads. The formulation, characterization, and stability of TA(+) mRNA LNPs are described; two different approaches via confocal microscopy are then utilized to quantify the endosomal escape of the TA(+) mRNA LNPs; and lastly, the biodistribution and tolerability of the TA(+) mRNA LNPs are evaluated in mice following intravenous and intramuscular dosing regimens. To isolate the effect that TA imparts on each of these properties, mRNA LNPs that do not contain TA [TA(−) mRNA LNPs] are evaluated side‐by‐side in each of these studies. A collective analysis of these results suggests that TA(+) mRNA LNPs are effective carriers for mRNA payloads and that the incorporation of TA within each formulation improves the endosomal escape of mRNA LNPs.

Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N-desbutyldronedarone: Application to prospective simulation of complex drug-drug interaction with rivaroxaban.

Despite potential enzyme- and transporter-mediated drug-drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N-desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations. The middle-out development of our PBPK model combined literature-derived or in-house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4- and P-glycoprotein-mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban-specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P-glycoprotein were incorporated into the PBPK-DDI model for prospective dronedarone-rivaroxaban DDI simulation. Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto-inactivation on dose nonlinearities. Following successful model validation, nondose-adjusted rivaroxaban-dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration-time curve up to 24 h fold change greater than dose exposure equivalence (0.70-1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban-ketoconazole DDI. Our PBPK-DDI model predicted clinically significant dronedarone-rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.

Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii.

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.

Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model.

The antitumor effects of two intravenous dosing regimens of Chol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in the Chol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then, let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution of Chol-let-7a and Chol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital. Continuous treatment with Chol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in the Chol-miRCtrl and blank xenograft group (P < 0.01 and P < 0.01, respectively), while intermittent dosing with Chol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in the Chol-miRCtrl and the blank control group, respectively (P < 0.05 and P < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosing Chol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues; mild hypercellularity with dilated capillary lumens in the renal tissue; and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed that Chol-let-7a and Chol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration of Chol-let-7a and Chol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in the Chol-miRCtrl group. Finally, RT-PCR analysis showed that let-7a levels were significantly increased in Chol-let-7a-treated xenografts compared with Chol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001); however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively. Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy. Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future.

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation.

Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phaseI and eight phaseIII studies, to determine the exposure-response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840mg q2w, 1200mg q3w, and 1680mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose-linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840mg q2w, 1200mg q3w, and 1680mg q4w for single-agent and combination therapy use in the USA and EU.

A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.

TPS3175 Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.

Intravenous Oxytocin Dosing Regimens for Postpartum Hemorrhage Prevention Following Cesarean Delivery: A Systematic Review and Meta-Analysis

(Am J Obstet Gynecol. 2021;225:250.e1–250.e38. [Epub May 4, 2021]) Postpartum hemorrhage (PPH) is a leading cause of maternal mortality. A common cause of PPH is uterine atony. To decrease the nearly 20% of 295,000 worldwide maternal deaths from PPH, there has been an increase in the use of uterotonics for all women during delivery. In 2018 the World Health Organization (WHO) recommended 10 IU of oxytocin to be administered to all women for both vaginal and cesarean deliveries (CD) to improve uterine atony and prevent PPH. There is insufficient evidence that 10 IU was an optimal amount for both types of delivery and the dose was based on insufficient evidence from an outdated Cochrane systematic review. The purpose of this review was to analyze the dosing regimens of IV oxytocin used for CD and to determine if any regimens are superior to others.

Pharmacokinetic-Pharmacodynamic Study of Ampicillin-Cloxacillin Combination in Indian Thoroughbred Horses (Equus caballus) and Safety Evaluation of the Computed Dosage Regimen

The pharmacokinetics of ampicillin-cloxacillin, given as single intravenously dose of 10 mg.kg−1 (5 mg.kg−1 of ampicillin plus 5 mg.kg−1 of cloxacillin) was examined in clinically presented Indian thoroughbred horses (n = 6) in order to design appropriate dosing strategies. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were derived by non-compartmental analysis using WinNonlin software. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ampicillin-cloxacillin against quality control strains of Escherichia coli and Staphylococcus aureus, grown in Muller Hinton Broth, were determined by broth microdilution method. For ampicillin, area under plasma drug concentration time curve (AUC) was 15.2 ± 0.54 µg.h.ml−1, mean residence time (MRT) was 1.33 ± 0.06 h and clearance (Cl) was 0.33 ± 0.01 L.h−1.kg−1. For cloxacillin, AUC was 18.0 ± 0.9 µg.h.ml−1, MRT was 1.28 ± 0.02 h and Cl was 0.28 ± 0.01 L.h−1.kg−1. MIC of ampicillin-cloxacillin combination against E. coli and S. aureus was determined to be 0.4 µg.ml−1. PK-PD integration indicated that to maintain %T > MIC value 50% for bacteria with MIC ≤ 0.4 µg.ml−1, an appropriate intravenous dosage regimen of ampicillin-cloxacillin combination in horses would be 15 mg.kg−1 (i.e. 7.5 mg.kg−1 of ampicillin plus 7.5 mg.kg−1 of cloxacillin), to be repeated at 12 h intervals. Safety profile of the recommended regimen did not significantly alter any of the 16 biochemical or haematological parameters studied.

Pharmacokinetic modeling and simulation to understand diamorphine dose-response in neonates, children, and adolescents.

Pharmacokinetic-pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure-response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children. Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure-response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6-monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time-concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1mg.kg-1 was similar to that after intranasal diamorphine 5mg in adults. A target concentration of morphine 30μg.L-1 can be achieved by a diamorphine intravenous infusion in neonates 14μg.kg-1 .h-1 , in a 5-year-old child 42μg.kg-1 .h-1 and in an 15year-old-adolescent 33μg.kg-1 .h-1 .