IV Administration Research Articles

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

A first-in-human trial of selective CDK7 inhibitor Q901, in patients with advanced solid tumors: Interim results of a phase I study (QRNT-009).

3078 Background: Q901 is a potent, covalently binding CDK7 inhibitor with excellent specificity for CDK7 against other protein kinases. Transcriptional regulation by CDK7 inhibition in cancer cells leads to DNA damage repair response inhibition and increased genomic instability. Q901 also regulates cell cycle checkpoints by inhibiting T-loop phosphorylation and transcriptionally downregulating CDK1, 2 and 4. In preclinical in vivo models, intravenous (iv) administration of Q901 once a week and once every three-week dosing regimen was well tolerated and showed significant antitumor activity. The safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy data for 18, 36 and 60 mg/m2 are presented. Methods: QRNT-009 (NCT05394103) is an ongoing Phase 1/2 multicenter, open-label, dose escalation and expansion study. Q901 is administered iv once weekly for four weeks, then once every two weeks thereafter in patients with advanced or metastatic ovarian cancer, castration-resistant prostate cancer (CRPC), breast cancer, endometrial cancer, colorectal cancer, small cell lung cancer (SCLC), or pancreatic cancers. Results: As of data cutoff (12Jan2024), 17 patients received Q901 across 3 dose levels: 5 patients at 18 mg/m2, 4 patients at 36 mg/m2, and 8 patients at 60 mg/m2. The median prior lines of systemic therapy were 4 (range 2 - 17). Of 17 patients who received Q901 across all doses, there were no treatment related SAEs, treatment discontinuations, or dose reductions. Most common TRAEs ≥ 15% were nausea (29.4%), anemia (23.6%) and fatigue (23.5%). As of data cutoff, no DLTs were observed. All plasma PK analyses across dose levels showed dose dependent increase of AUC0-last and Cmax. No major metabolite was observed. POLR2A, which is a CDK7 target engagement marker showed biologically effective change starting from 18 mg/m2. 1 patient with pancreatic cancer who received 18 mg/m2 had a partial response with CA19-9 reduction from 4,632 to 219. 2 patients at 18 mg/m2 and 2 patients at 36 mg/m2 had stable disease. Additional safety and efficacy data will be presented. Conclusions: Preliminary data from QRNT-009 study showed that selective CDK7 inhibitor Q901 is well tolerated. Preliminary antitumor activity and pharmacodynamic observations are encouraging. Dose escalation is ongoing to identify MTD or recommended dose for further studies. Clinical trial information: NCT05394103 .

HCM AT THE CROSSROAD

Abstract Introduction Treatment of oHCM frequently requires difficult choices, especially when it is superimposed on other urgent clinical conditions,such as AMI or mechanical complications. Clinical Case A 52–year–old man with known oHCM, who spontaneously quickly discontinued recommended therapy, presents to theED with a sudden episode of dyspnea and presyncope. A firstECG was essentially normal for pathology. After 1h, the patient experiences a sudden episode of chest pain with rapid hemodynamic deterioration and cardiogenic shock(CS). The ECG shows changes compatible with inferolateral MI. The TTE shows severe LVOTO, SAM, severe MR and a suspicious oval image attached to the anterior mitral leaflet. The patient underwent orotracheal intubation, coronary angiography and TEE. Coronary angiography shows a thrombotic occlusion of the proximal circumflex artery, treated with pPCI. TEE confirms a partial rupture of the papillary muscle head. Treatment:The patient‘s CS can be caused by 2different conditions that require treatments with opposing pathophysiological principles. SevereMR due to papillary muscle rupture, as mechanical complication of MI, requires afterload reduction, hemodynamic stabilization with IABP and emergency transfer to a cardiac surgery center. In contrast, the treatment of the underlying pathology(severe LVOTO and severe rMR due to SAM)requires pharmacological stabilization with depression of cardiac contractility and increase in afterload. In the context of cardiogenic shock a rapid choice was required. To help us make the right choice, an Esmolol test was performed. After iv administration of 2mg Esmolol, heart rate was reduced without reduction in BP. The patient was then treated with esmolol in continuous infusion and norepinephrine. In oHCM the ventriculo–arterial coupling is reduced, less than 1. This treatment favored better V–A coupling, ensuring an increase in afterload and a reduction in myocardial contractility. The patient‘s clinical condition rapidly improved, allowing extubation at48h and early mobilization at96h. Myectomy and mitral repair surgery was scheduled 1 month afterPCI. Conclusions Through the use of a short–lived drug such as Esmolol, it was possible to trace the prevailing mechanism of the patient‘s CS. Differently from other cases of CS, to rebalance the V–Acoupling, it was crucial to reduce myocardial contractility and increase afterload. A pathophysiological pharmacological approach ensured a good outcome.

Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs

BackgroundProteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known.MethodsA typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14C-A947 (BRM degrader)—was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties.ResultsHere, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2–3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors.ConclusionsPlasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

Intranasal and intravenous apomorphine outperform ropinirole ocular drops for induction of emesis in dogs within ten minutes: a randomized, controlled clinical trial.

The primary goal was to compare the efficacy of administration of apomorphine (APO) administered by intranasal (IN), transconjunctival (TC), SC and IV routes with ropinirole eye drops for induction of emesis in dogs with a secondary goal to evaluate the time of emesis as well as difficulty in administration. 125 client-owned dogs. Dogs were randomly enrolled between October 1, 2021, and March 30, 2022, into groups of 25: IV APO, IN APO, TC APO, SC APO, and ropinirole eye drops. The IV, SC, and TC groups were dosed at 0.03 mg/kg, the IN group was dosed at 0.06 mg/kg, and the ropinirole group was dosed according to manufacturer guidelines. Data collected included success rate of emesis within 600 seconds, time to emesis, time to administer, and difficulty score. Results were compared to IV with P values and CIs being adjusted for multiple comparisons. Emesis was successful within 600 seconds using IV APO in 22 of 25 dogs. By comparison, IN APO induced emesis in 18 of 25 dogs (P = .63). Ropinirole (14/25), SC APO (6/25), and TC APO (4/25) were significantly less successful (P = .047, P = < .001, and P < 0.001, respectively). When emesis was successful, it occurred most rapidly with TC APO, followed by IN APO and then ropinirole. It was most difficult to administer IV APO and TC APO. Similar to IV APO, IN APO was a rapid, easy, and effective method of inducing emesis in dogs and should be considered when IV administration is not possible. Ropinirole was easy to administer but successfully induced emesis less reliably within a 10-minute timeframe. APO administered TC using the commercially compounded injectable formulation was ineffective.

Valoración de la transición de vedolizumab intravenoso a subcutáneo en pacientes con enfermedad inflamatoria intestinal

AimsThe aim of the study is to evaluate the clinical and biochemical response of inflammatory bowel disease patients treated with vedolizumab, 16 weeks after transitioning from intravenous (iv) to subcutaneous (sc). MethodsAn observational, prospective, single-center cohort study was performed. Patients with inflammatory bowel disease and maintenance treatment with vedolizumab, stable for at least 4 months, were offered to switch to sc formulation. At the same time of treatment administration a blood test was performed, with vedolizumab levels and fecal calprotectin. ResultsForty-three patients were included, 12 of them (27.9%) chose to transition to sc formulation. All included patients remained in remission during follow-up. At week 16 no significant differences were found in terms of calprotectin levels in patients on iv treatment (mean 146.6±SD 45.9) vs. sc (159.26±53.9) (p=0.9). Vedolizumab serum levels at week 16 were higher in the sc group (22,364.3±5141.6) vs. iv (11,425.9±1514.2) (p=0.009). At week 16, 9 (75%) of the patients in the sc group were highly satisfied with the medication and 11 (91.7%) considered it easy to administer. Four patients (12.9%) in the iv group and 2 (16.6%) in the sc group presented mild adverse effects. The 2 cases (100%) of the sc group the adverse event was local inflammation at the injection site. ConclusionIn our experience, vedolizumab sc is a convenient alternative to iv administration. Vedolizumab serum levels in patients who transitioned to sc were higher than iv formulation.

Pharmacokinetics of amikacin after intravenous, intra-articular, and combined intravenous and intra-articular administration in healthy neonatal foals.

Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra-articular (IA) administration. Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. Eight healthy neonatal foals. Foals received 3 amikacin treatment protocols: (1) IV-only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA-only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. Foal age was a significant variable. The IV-only protocol met or exceeded the 30-minute plasma concentrations considered therapeutic (mean μg/mL [95% confidence interval, CI]) in 7- to 9-day-old (54.0 [52.2-56.9]), 14- to 16-day-old (58.1 [55.2-61.0]), and 21- to 23-day-old (66.6 [63.7-69.6]) foals. Concurrent IV and IA protocol did not reach the 30-minute concentration considered therapeutic in 7- to 9-day-old foals (46.5 [43.6-49.4]) but did in 14- to 16-day-old (62.9 [60.0-65.8]) and 21-to 23-day-old (62.6 [59.7-65.6]) foals. Concurrent IV and IA administration of amikacin produces 30-minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.

No Measurable Transfer of Oxytocin-Receptor Agonist Merotocin Detected in Human Breast Milk.

Objective: The study aimed to assess the transfer of merotocin from systemic circulation to breast milk in early postpartum women and women with established lactation. Methods: This was a two-part, multicenter, open-label, parallel-group study. Merotocin was administered as a single 90-minute intravenous (iv) infusion mimicking the intranasal pharmacokinetic profile. In Part A, 12 early postpartum women received doses of either 4 μg (n = 6) or 16 μg (n = 6) of merotocin within 4 days of delivery. In Part B, six women with established lactation received 20 μg of merotocin. The total concentration of merotocin in plasma and breast milk and its metabolites excreted in breast milk were measured at various time points. Adverse events (AEs) were also assessed for both parts of the study. Results: In both early postpartum and established lactation groups (mean age, 26.3 years; 83.3% Caucasian), merotocin and its metabolites in breast milk were below the limit of quantification (25.0 pg/mL) at all time points. Sixteen treatment-emergent AEs occurred in early postpartum women only, including seven events of uterine spasm and three of breast engorgement. There was one moderate event, whereas all the other events were considered mild. Conclusion: Merotocin was undetectable in breast milk after single iv administration of up to 20 μg in early postpartum women and women with established lactation.

Abstract 5341: Novel FcγR humanized mouse model enables assessment of PK/PD of therapeutic antibodies

Abstract Therapeutic antibodies have revolutionized the way we treat cancer. Enhanced activity of therapeutic IgG can be achieved by the modulation of Fc binding to Fcγ receptors (FcγR), which will consequently modulate the Fc-effector functions triggered upon crosslinking of target and effector cells by these antibodies. Assessment of therapeutic antibodies pharmacodynamic (PD) in preclinical models is challenging, as the FcγR are different from mice to human, as well as their expression pattern. FcRn is involved in the recycling and transport of IgG and is a key determinant of the pharmacokinetics (PK) of IgG. We report here a novel mouse model expressing human FcγR with a human-like expression pattern, in which human FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB are expressed and replace their mouse orthologs. The model was intercrossed with the hSA/hFcRn mouse model (Viuff et al., 2016), which has shown to improve translatability of PK assessment of therapeutics with extended half-life via FcRn recycling and/or HSA binding. Investigation of FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB expression on DC, monocytes, granulocytes, NK, T and B cells shows that expression pattern in hFcγR mice is consistent with their expression on human PBMC, with a few exceptions. These receptors are functional, as a human IgG1 targeting mouse CD20 induces approximately 50% of B-cell depletion in blood and liver, after a single iv administration in hFcγR mice. This depletion is Fc-mediated, as it is abrogated when hFcγR mice are treated with an anti-mouse CD20 human IgG1 with a Fc-null mutation. Assessment of antibody-dependent cell cytotoxicity (ADCC) ex vivo to investigate FcγR functionality in NK cells shows that Rituximab, an anti-human CD20 chimeric IgG1 with regular Fc, induces higher ADCC efficacy in NK cells from hFcγR than in NK cells from WT mice. Obinutuzumab, an anti-human CD20 featuring an optimized Fc portion to enhance binding to FcγRIII, shows higher tumor cell lysis than Rituximab in NK cells from hFcγR mice, suggesting this model enables ranking of antibodies. Moreover, assessment of activity of Fc-engineered anti-influenza IgG antibodies also shows that anti-Flu antibody with enhanced Fc binding outperforms the WT antibody, improves protective activity, and demonstrates effector function in influenza challenge model, following prophylactic treatment. Conversely, hFcγR mice treated with an Fc-null version of the anti-Flu antibody shows reduced protective activity and survival compared with the WT antibody. Therefore, the model reported here is a novel tool for testing efficacy of Fc-engineered therapeutic antibodies. We are currently investigating the PK profile of therapeutic antibodies in the hFcγR/hSA/hFcRn model. This novel tool is being improved to enable tolerability to human IgG1, biodistribution to the central nervous system, and flexibility of test of therapeutics through expression of human immune checkpoints. Citation Format: Fabiane Sonego, Angela Pappalardo, Gaëlle Martin, Rachel Courtois, Séverine Augier, Yacine Cherifi, Ariane Morel, Patricia Isnard-Petit, Kader Thiam. Novel FcγR humanized mouse model enables assessment of PK/PD of therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5341.

Abstract 736: ACTM-838 safely and comprehensively re-activates the immunosuppressive TME by exploiting myeloid biology intrinsic in many cancers

Abstract ACTM-838 is a genetically modified bacterial vehicle encoding a DNA plasmid with two engineered payloads, IL-15plex and constitutively active eSTING. The bacterial vehicle is a highly attenuated S. typhimurium, engineered to facilitate safe IV administration. ACTM-838 is designed to specifically enrich in the TME via auxotrophic dependency on extracellular adenosine and purine metabolites. ACTM-838 is then selectively internalized by tumor-resident myeloid cells achieving tumor-specific payload delivery. Previously, we showed ACTM-838 exhibited significant and durable anti-tumor efficacy across syngeneic tumor mouse models (EMT6 breast, MC38 colon) and MMTV-PyMT GEMM. To elucidate TME changes induced by ACTM-838, EMT6 tumors were analyzed post-treatment by scRNA-seq, which demonstrated that ACTM-838 induced significant transcriptional changes in several cell populations in the TME. Cytolytic pathways were upregulated in T and NK cells, while type I IFN and PDL1 were upregulated in myeloid populations consistent with previous bulk RNAseq analyses. To understand the tolerability and safety of ACTM-838, a GLP toxicology study was performed on naïve cynomolgus monkeys (NHP). No ACTM-838-related clinical or veterinary observations were reported at any dose level. Acute dose-dependent increases in serum cytokines were observed at 4 hours which reverted to baseline by 24 hours. ACTM-838 was cleared from blood by 24 hours post-dose with no significant shedding in urine or feces. ACTM-838 was only detected in the spleen in 2 and 1 animals at 22- and 49-days post treatment, respectively. Pre-existing ADA was observed in some animals with subsequent increases in ADA upon dosing in most animals. However, no correlation of serum ADA and blood PK levels suggested that the presence of ADA does not impact drug stability. The ACTM-838 mechanism of action requires high levels of adenosine or purine metabolites to enrich and colonize the TME as well as phagocytic internalization by tumor-intrinsic myeloid cells to achieve tumor-specific payload delivery. Myeloid cells comprise roughly half of all cells in the TME in human tumors. Bioinformatics analyses of the public patient datasets identified key tumor indications enriched in both adenosine and myeloid pathways. To further understand the spatial heterogeneity in the TME across tumors, we performed multiplex immunofluorescence on patient tumor microarrays to validate tumor types with a high prevalence of myeloid populations coupled with an active adenosine pathway, which will help guide future clinical study design. In summary, we demonstrate that ACTM-838 modulates the TME and is stable and safe in animal models. Additionally, our studies recommend the prioritization of certain tumor indications for treatment with ACTM-838 in the clinic. Citation Format: William Lu, Kyle Cron, Julie Janes, Leigh Berryman, Gurvinder Singh, Christopher Thanos, Akshata Udyavar. ACTM-838 safely and comprehensively re-activates the immunosuppressive TME by exploiting myeloid biology intrinsic in many cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 736.

Abstract WMP30: Real World Experience With Tenecteplase on a Mobile Stroke Unit

Background: Tenecteplase (TNK) administered on a mobile stroke unit (MSU) has demonstrated superior rates of early reperfusion compared to alteplase. Current guidelines include TNK as a second-tier option for large vessel occlusions as TNK has many benefits, including rapid IV administration and ease of dosing. The objective of this study was to describe real world utilization of TNK on a MSU. Methods: This was a retrospective observational study of patients receiving TNK as compared to alteplase between February 2021 and April 2023 at a large academic comprehensive stroke center. Baseline demographics, GCS, NIHSS, as well as time of initial imaging were collected. Primary endpoint was time from MSU door to thrombolytic administration. Secondary endpoints included: MSU door to imaging interpretation, dispatch to thrombolytic administration, and provider decision time to thrombolytic administration. Safety endpoints included symptomatic ICH within 24 hours. Results: During the studied time period 40 patients received alteplase and 32 patients received TNK on the MSU. The median age was 65.7 years and median NIHSS score was 9. There was no difference in time from MSU door to thrombolytic administration (15 vs 17.5, p=0.30). There was also no difference in time from MSU door to imaging interpretation, dispatch to thrombolytic administration, or provider decision time to thrombolytic administration. No hemorrhagic conversion occurred. Conclusion: This is the largest series to date describing real-world utilization of TNK administration in a MSU. There were no significant differences in time to therapy in any of the time points evaluated. This data is promising for the treatment of ischemic stroke in which time to administration of thrombolytic therapy is paramount and TNK is administered as a rapid IV injection as compared to alteplase infusion.

P797 Assessment of pharmacokinetics and clinical response in patients transitioning from intravenous to subcutaneous vedolizumab

Abstract Background Vedolizumab is a humanized monoclonal antibody directed against α4β7 integrin used in inflammatory bowel disease (IBS) patients1. The usual dosage of Vedolizumab is 300 mg intravenously (iv). Recently the subcutaneous (sc) formulation (108 mg every 2 weeks) has been approved, which provides more independence for the patient, avoiding visits to the hospital and possible inconveniences associated with it2. Methods The aim of the study is to evaluate the clinical and biochemical response of IBS patients treated with vedolizumab, 16 weeks after transitioning from iv to sc. An observational, prospective, single-center cohort study was performed. Patients with IBS and maintenance treatment with vedolizumab, stable for at least 4 months, were offered to switch to sc formulation. At the same time of treatment administration a blood test was performed, with vedolizumab levels and fecal calprotectin. Clinical index as Harvey-Bradshaw Index (HBI)/Simple Clinical Colitis Activity Index (SCCAI) and questionaries (IBDQ-9 and TSQM) were performed on each visit. Results 43 patients were included, 12 of them (27.9%) chose to transition to sc formulation. Baseline characteristics of both groups are shown in Table 1. 34 (79.1%) patients were prescribed vedolizumab due to previous biologic failure, 7 (16.3%) in first line due to comorbidities and 2 (4.7%) because of adverse effects in prior treatment. All included patients remained in remission during follow-up. At week 16 (w16), no significant differences were found in calprotectin levels in patients on iv treatment (mean 146.6 ± SD 45.9) vs sc (159.26 ± 53.9) (p 0.9). Vedolizumab serum levels at w16 were higher in the sc group (22364.3 ± 5141.6) vs. iv (11425.9 ± 1514.2), with statistically significant differences (p 0.009). At w16, 9 (75%) of the patients in the SC group were highly satisfied with the medication and 11 (91.7%) considered it easy to administer. 1 patient (8.3%) in the sc group returned to iv treatment. 4 patients (12.9%) in iv and 2 (16.6%) in sc treatment presented mild adverse effects. The 2 cases (100%) of the sc group the adverse event was local inflammation at the injection site. Conclusion In our experience, vedolizumab sc is a safe and convenient alternative to iv administration. Vedolizumab serum levels in patients who transitioned to sc were higher than iv formulation. 1. Smith, Michael A et al. "Vedolizumab: an α4β7 integrin inhibitor for inflammatory bowel diseases." The Annals of pharmacotherapy vol. 48,12 (2014): 1629-35. 2. Vermeire, Séverine et al. "Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial." Journal of Crohn's &amp; colitis vol. 16,1 (2022): 27-38.

Роль корекції ендотеліальної дисфункції в комплексній профілактиці гіпертензивних ускладнень вагітності

Purpose - to study the effect of correction of endothelial dysfunction by the introduction of L-arginine in the comprehensive prevention of the development of severe hypertensive disorders in pregnant women. Materials and methods. The division into groups was carried out indiscriminately following the prescribed bath. 27 women reached the 1st group, who, in addition to basic prevention of preeclampsia (small doses of aspirin for 12 days, calcium supplement 1000 mg per dose for 16 years), took Tivortin until conception and p. It's an hour of urgency; up to the 2nd group - 54 women who did not receive basic prevention of preeclampsia. The control group (3) consisted of 16 healthy women with physiological changes in vagusity. Participants of the 1st group, during the hour of stay in the hospital, took L-arginine internally (iv) (4 g) + 2 teaspoons 2 times (4 g) per os per dose 40 minutes before admission, then 3 teaspoons spoons 2 times (6 g per dose). The average intensity of the droplets became 6. The function of the endothelium was evaluated according to the universally recognized non-invasive cuff test method, which is based on the principle of ultrasound assessment of the change in the diameter of the brachial artery in response to the restoration of blood flow in it after short-term compression of the upper limb with a cuff. Physical condition and endurance were assessed using the generally accepted 6-minute walk method. The quality of life in pregnant women who had experienced severe preeclampsia in the past was assessed in stages - according to the health-related quality of life (HRQoL) scale and the scale created by the World Health Organization (WHOQOL-BREF). Results. Arterial hypertension and preeclampsia are based on changes in endothelium-dependent vasodilatation. A positive effect on the function of the endothelium significantly improves indicators of physical well-being and quality of life. When conducting a test with a 6-minute walk in the Group 1, better indicators were found than in the Group 2 (respectively, 409±23 m vs. 381±32 m, p&lt;0.05), this indicator in the control group was 473±32 m (p&lt;0.05 according to the Groups 1 and 2). However, this indicator significantly improved in pregnant women of the Group 1 after intravenous administration of L-arginine: 441±12 m (p&lt;0.05 compared to the indicator before intravenous administration). According to the assessment of the quality of life of pregnant women of the studied groups, it should be noted that the quality of life indicators in all domains are significantly lower in women of the Group 1, which is associated with significantly worse anamnesis data of such women, significant concern about the results of the next pregnancy. When evaluating indicators of endothelium-dependent and endothelium-independent vasodilatation, it was found that in the group of women who received L-arginine preconceptionally, in the 1st trimester, the indicator before intravenous IV administration was 5.09±0.44, and after - 8.21±0.24, which indicates a significant improvement in endothelium-dependent vasodilation indicators (by 49.1%) 28-32 weeks, there are also no births of children with a body weight of less than 1500 g. Conclusions. In the group of high-risk pregnant women, the use of L-arginine in the complex prevention of preeclampsia allows to reduce the risks of early severe preeclampsia, to reduce the medication burden of two- and three-component hypotensive therapy. An increase in physical endurance, quality of life, and improvement in pregnancy outcomes are due to a positive effect on the function of the endothelium through the optimization of endothelium-dependent vasodilatation associated with the provision of the L-arginine substrate for the full synthesis of nitric oxide. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2

Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 in mice yet drives low levels of type-1 IFNs but robust IFNγ. Here we examine the role of ongoing IFNγ responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFNγ receptor expression by non-hematopoietic cells. Importantly, we show that BCG infection prompts pulmonary epithelial cells to upregulate IFN-stimulated genes with reported anti-viral activity in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFNγ by demonstrating that the recombinant cytokine itself provides strong protection against SARS-CoV-2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.

Daratumumab, Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Asian Patients with Newly Diagnosed Multiple Myeloma: Final Analysis of the Phase 3 Octans Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action and has shown clinical efficacy for the treatment of multiple myeloma (MM). In an updated analysis of the global phase 3 ALCYONE study, D-VMP demonstrated a significant progression-free survival (PFS) benefit compared to VMP in transplant-ineligible patients with newly diagnosed MM (NDMM). A prior analysis of the phase 3 OCTANS study (median follow-up, 12.3 months) also showed a favorable clinical benefit/risk profile for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM. Here, we report results from the final analysis of OCTANS, with a median follow-up of &amp;gt;3 years. Methods: The randomized, phase 3 OCTANS study (NCT03217812) enrolled Asian patients with NDMM who were ineligible for autologous stem-cell transplant due to age or presence of comorbidities. Patients were randomized 1:2 (VMP:D-VMP) to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 weeks in Cycles 2-9, and every 4 weeks thereafter until disease progression). Per a protocol amendment, patients receiving daratumumab IV were permitted to switch to daratumumab SC 1,800 mg (same schedule as IV) on Day 1 of any cycle. The primary endpoint was achievement of a very good partial response (VGPR) or better. Results: A total of 220 patients were randomized to D-VMP (n = 146) or VMP (n = 74). At the time of the final analysis, with a median follow-up of 41.2 months, the rate of VGPR or better was significantly higher with D-VMP versus VMP (80.1% vs 47.3%; P &amp;lt;0.0001; Table). The rate of measurable residual disease negativity (10 -5) was also higher with D-VMP versus VMP (40.4% vs 10.8%; P &amp;lt;0.0001). D-VMP continued to show a significant improvement in PFS versus VMP (median, 38.7 vs 19.2 months; HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001; Table, Figure), as well as a longer time to subsequent antimyeloma therapy (median, 46.8 vs 20.6 months; HR, 0.31; 95% CI, 0.20-0.47; P &amp;lt;0.0001). However, median overall survival was not yet reached for either group. The overall safety profile of D-VMP was consistent with that observed for the primary analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 133 (92.4%) patients who received D-VMP and 60 (84.5%) patients who received VMP and were primarily hematologic events; nonhematologic grade 3/4 TEAEs in ≥10% of patients included pneumonia (D-VMP, 31.3% vs VMP, 18.3%), hypokalemia (15.3% vs 4.2%), and hypertension (13.2% vs 8.5%). Grade 3/4 infection TEAEs were reported for 67 (46.5%) and 22 (31.0%) patients who received D-VMP or VMP, respectively. Serious TEAEs were reported for 75 (52.1%) and 28 (39.4%) patients in the D-VMP and VMP groups, respectively, and TEAEs led to treatment discontinuation in 6 (4.2%) and 4 (5.6%) patients, respectively. The incidence of infusion-related reaction TEAEs in the D-VMP group was 33.3%, which is consistent with that previously reported for daratumumab; most events were of grade 1 or 2 severity. The risk of immunogenicity to daratumumab was low, with 1 of 130 evaluable patients testing positive for daratumumab antibodies. Within the D-VMP group, 76 patients switched from daratumumab IV to SC administration. Among these patients, 64 (84.2%) patients preferred SC administration, 7 (9.2%) preferred IV administration, and 15 (19.7%) had no preference on ≥1 of 2 surveys. Of the 64 patients who preferred SC administration, primary reasons included treatment administration time (84.4%), more comfortable administration process (57.8%), less caregiver burden (31.2%), and fewer administration-related reactions (26.6%). Conclusions: With a median follow-up of &amp;gt;3 years, this final analysis of OCTANS demonstrated a continued clinical benefit with D-VMP versus VMP in Asian patients, with PFS improvement comparable to that observed in the global ALCYONE study (HR, 0.35 vs 0.42, respectively). No new safety concerns were identified for D-VMP with extended follow-up. In addition, daratumumab SC administration was preferred by the majority of patients who switched from daratumumab IV. These results further support the use of daratumumab IV or SC in combination with VMP in transplant-ineligible Asian patients with NDMM.

HIV Comorbid Infection and Liver-Directed AAV-Based Gene Therapy in Adults with Severe and Moderately Severe Hemophilia B: Efficacy and Safety Results from Phase 2b and the Pivotal Phase 3 HOPE-B Trials 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec

Introduction: People living with HIV represent an important subset within the hemophilia community. Concerns about increased hepatotoxicity of liver-directed adeno-associated viral (AAV) vectors in patients receiving potentially hepatotoxic HIV medications (eg, efavirenz) have excluded this population from participating in many of gene therapy hemophilia trials. However, adult patients with hemophilia B (PwHB) with controlled HIV comorbid infection were not excluded from enrollment in phase 2b (NCT03489291) and phase 3 HOPE-B (NCT03569891) trials evaluating the efficacy and safety of etranacogene dezaparvovec (formerly AMT-061), an AAV5 vector containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of the liver-specific promoter LP-1. Aim: The aim of this ad hoc analysis was to evaluate the efficacy and safety of etranacogene dezaparvovec in the subset of adult PwHB with comorbid infection with HIV from both the phase 2b and the phase 3 HOPE-B trials. Methods: A single IV administration of 2x10 13 gc/kg etranacogene dezaparvovec was administered to adult patients with severe or moderately severe hemophilia B in phase 2b and phase 3 HOPE-B trials. Patients with HIV infections uncontrolled by antiviral therapy demonstrated by CD4+ counts ≤200/µL were excluded from the studies. Individual safety and efficacy outcomes of participants with controlled HIV infection treated with etranacogene dezaparvovec were assessed. Liver enzyme levels and aPTT-based FIX activity levels were analyzed by a central laboratory. Descriptive statistical analyses were used to report all results with a data cut at 3 years post administration of etranacogene dezaparvovec. Results: Among 57 participants who received etranacogene dezaparvovec in phase 2b and phase 3 HOPE-B trials, 5 had comorbid HIV infection (median [range] age 49 years [38-54]), of whom 4 had a history of treated hepatitis C virus with a negative viral load. Three out of 5 participants with comorbid HIV infection had pre-existing AAV5 neutralizing antibodies with median [range] titer of 20 [0-99]. Annualized bleeding rate (ABR) decreased post treatment compared with previous FIX prophylaxis regimen (with extended half-life FIX products) for all HIV+ patients; median [range] ABR during FIX prophylaxis was 5 [1-10.4]. Two patients recorded no bleeds in the 36 months after receiving etranacogene dezaparvovec treatment, and the overall median [range] ABR post treatment was 0.64 [0-5.0]. FIX activity levels in these participants were apparent from week 3 and were maintained in the mild/normal range for 4/5 (80%) participants (Figure 1). Median [range] uncontaminated endogenous FIX at 3 years post treatment was 32.3% [31.5%-58%]. Two patients had contaminated FIX measurements at 36 months (1 returned to prophylaxis shortly after 24 months and the other took on-demand replacement therapy the day before the 36-month visit). No treatment-related serious adverse events (AEs) occurred. Only 7 treatment-related AEs were reported in 3 participants. Treatment-related ALT elevation of moderate severity occurred in Participant 5 (20%, similar to patients without HIV comorbid infection) at 35 days post treatment and resolved within 15 days with the use of corticosteroids. This patient eventually had his FIX levels declined to 2-5% range; his bleeding phenotype returned, and he resumed prophylaxis per protocol at month 30 post-treatment. Annualized FIX use (IU/year) was reduced between 34% and 100%, with 3 participants who received no FIX infusions through 36 months post treatment. Conclusion: Etranacogene dezaparvovec were observed to be safe and effective in a subset of study participants living with HIV. These results support the use of etranacogene dezaparvovec, the first approved liver-directed AAV-based gene therapy product for the treatment of patients with severe or moderately severe hemophilia B in the US and Europe, for eligible patients with controlled comorbid HIV infection. Owing to the small number of patients with HIV being enrolled in trials, long-term collection of data and special attention in the real-world setting is recommended.

Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) Alone in Chinese Patients with Relapsed/Refractory Multiple Myeloma: Final Analysis of the Phase 3 Lepus Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. D-Vd prolonged progression-free survival (PFS) and induced deeper and more durable responses versus Vd alone in patients with relapsed/refractory multiple myeloma (RRMM) in the global phase 3 CASTOR study. A prior updated analysis of the phase 3 LEPUS study (median follow-up, 25.1 months) showed significant clinical benefit for D-Vd versus Vd in Chinese patients who have RRMM, and a safety profile generally consistent with that observed in CASTOR. Here, we report results from the final analysis of LEPUS with an extended median follow-up of &amp;gt;3 years. Methods: In the randomized, multicenter, phase 3 LEPUS study (ClinicalTrials.gov Identifier: NCT03234972), Chinese patients with RRMM who had received ≥1 prior line of therapy were randomized 2:1 to 8 cycles (21 days/cycle) of Vd (bortezomib 1.3 mg/m 2 SC on Days 1, 4, 8, and 11; dexamethasone 20 mg PO/IV on Days 1, 2, 4, 5, 8, 9, 11, and 12) ± daratumumab (16 mg/kg IV weekly in Cycles 1-3, every 3 weeks in Cycles 4-8, and every 4 weeks thereafter until disease progression). Per a protocol amendment, on Day 1 of any cycle patients receiving daratumumab IV were permitted to switch to daratumumab SC 1800 mg (same schedule as IV). The primary endpoint was PFS. Results: A total of 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a median follow-up of 37.1 months, D-Vd continued to prolong PFS versus Vd alone (median, 14.9 vs 6.3 months; hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.25-0.52; P &amp;lt;0.00001; Figure 1). Time to progression (median, 15.7 vs 6.8 months; HR, 0.34; 95% CI, 0.23-0.51; P &amp;lt;0.00001) and overall survival (median, not reached vs 40.7 months; HR, 0.76; 95% CI, 0.50-1.17; P = 0.21; Figure 2) were longer with D-Vd versus Vd. The duration of response among patients who achieved a partial response or better was also longer with D-Vd versus Vd (median, 16.8 vs 9.0 months). The measurable residual disease-negativity rate (10 -5) was higher with D-Vd versus Vd (32.6% vs 4.3%; odds ratio, 10.81; 95% CI, 3.23-36.23; P &amp;lt;0.0001). The safety profile of D-Vd observed at the final analysis was generally consistent with that observed for the prior updated analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were primarily hematologic events. Grade 3/4 infections were reported for 77 (55.0%) patients who received D-Vd and 28 (41.2%) patients who received Vd; lung infection (30.7% vs 22.1%, respectively) was the only nonhematologic grade 3/4 TEAE reported in ≥20% of patients. For patients who received D-Vd and Vd, respectively, TEAEs were classified as serious for 76 (54.3%) and 27 (39.7%) patients, led to treatment discontinuation in 7 (5.0%) and 2 (2.9%) patients, and led to death in 6 (4.3%) and 7 (10.3%) patients. None of the 123 patients in the D-Vd group who had appropriate immunogenicity samples were positive for antibodies to daratumumab. A total of 31 patients in the D-Vd group switched from daratumumab IV to daratumumab SC during the study (after completion of bortezomib and dexamethasone); among these patients, 24 (77.4%) preferred SC administration, 2 (6.5%) preferred IV administration, and 5 (16.1%) had no preference. For the 24 patients who indicated they preferred daratumumab SC administration, key reasons for their preference included treatment administration time (83.3%), more comfortable administration process (70.8%), fewer administration-related reactions (45.8%), and less caregiver burden (25.0%). Among the 31 patients who switched to daratumumab SC, 6 (19.4%) patients experienced grade 3 TEAEs (most commonly hyperglycemia and hypokalemia, n = 2 each) and 2 (6.5%) patients experienced serious AEs (pyrexia and hyperglycemia, n = 1 each). Conclusions: In this final analysis of LEPUS with a median follow-up of &amp;gt;3 years, D-Vd continued to demonstrate substantial efficacy benefits versus Vd and the safety profile of D-Vd remained stable, with no new safety concerns identified. In addition, several patients switched their daratumumab administration from IV to SC, which was preferred by most patients who switched. These results further support the feasibility of daratumumab SC administration and the use of D-Vd as a standard of care in Chinese patients with RRMM who have received ≥1 prior line of therapy.

Updated Results from a Phase I Dose Escalation Study of the Rapidly-Switchable Universal CAR-T Therapy UniCAR-T-CD123 in Relapsed/Refractory AML

Introduction CAR-T efficacy in AML has been limited by a lack of ideal target antigens as well as the aggressive and resistant nature of disease. CD123 expression on leukemic blasts has been observed in about 80% of AML patients. However, the antigen is also expressed on non-malignant hematopoietic cells including neutrophils and endothelial cells. As consequence, targeting of CD123 with conventional CAR-T has been shown to result in persistent cytopenias, capillary leakage syndrome, CRS, and ICANS. AVC-101 (UniCAR02-T-CD123) is an adapter CAR-T, consisting of a universal CAR-T cell (UniCAR-T) and a CD123 targeting module (TM). The TM binds to the CAR-T cell via a peptide tag and induces T cell activity against CD123 bearing cells. Due to the short half-life of the TM, interruption of its continuous IV administration will rapidly switch T cell activity off, and mitigate toxicities as shown previously. Since the presentation of initial results, the study was amended to include a stricter and prolonged schedule of TM consolidation cycles. Given the excellent safety enabled by the switchable mechanism, additional dose levels (DL) of TM were added. Methods Key inclusion criteria included rrAML patients with ECOG ≤ 1, CD123 expression in ≥ 20% of blasts, and no suitable approved treatment option available or MRD positive AML patients. Initial dosing was applied using an adaptive Bayesian optimal interval design for drug-combination trials, escalating either cell dose or TM concentration based on posterior probability calculation of AEs. Dose escalation for the two additional dose levels was guided by a classical 3+3 design. Patients received standard Flu/Cy lymphodepletion (LD) for 3 days and TM was administered as continuous infusion, whereas UniCAR-T cells were given as one-time infusion on cycle 1 day 1. After completion of the initial 20-day induction cycle, responding patients were allowed to receive up to 3 consolidation cycles of 12 days continuous TM infusion with 7-14 days treatment free intervals in between cycles. Results As of this time 19 patients have received the induction cycle, 8 patients have also received at least one consolidation cycle (1-3, total 13 cycles). Patients were heavily pretreated with a median of 4 (2-7) prior treatment lines. Twelve of these patients had received a prior allogeneic (Allo) stem cell transplantation (SCT). Most of the patients (60%) were in adverse risk category according to ELN classification. In the initial escalation phase, 19 patients were treated in 16 dose cohorts. We observed a single DLT at DL 8 (reversible drop in fibrinogen levels, reported earlier) but no DLTs occurred in 11 patients treated in the yet highest dose cohort of 4 mg/day TM and 500 million UniCAR-T. Treatment was generally well tolerated irrespective of age and prior treatments. CRS was observed in 12 patients, mostly grade 1 or 2. Three grade 3 CRS and 1 grade 2 ICANS were reported, all resolving within 24 hrs from interruption of TM administration. Treatment-related AEs were most frequent in cycle 1, none were reported in cycles 3 and 4. No treatment-induced lasting myelosuppression was observed, and no patient required SCT support for WBC reconstitution. ORR in the first 19 patients was 53% (8/15) for the rrAML population and 75% (3/4) for the MRD population. Since the last presentation, extended administration of TM (20-day induction followed by three 12-day consolidation cycles 1-2 weeks apart) initiated by protocol amendment resulted in durable, ongoing responses approaching 5 months, longer than any prior. A 64-year-old MRD+ patient (#19) with 4 prior lines of therapy experienced a 3-log reduction in MRD levels (NPM1 mutation by qPCR) in both bone marrow and blood (Figure 1) and became transplant eligible. Re-administration of TM resulted in a significant re-expansion of UniCAR-T (Figure 2) without further cell dosing or LD. Another patient (#20) with overt hematological relapse after AlloSCT achieved a CR, ongoing at 5 months. Full safety and efficacy results of the additional 2 dose cohorts with prolonged TM consolidation will be presented at the meeting. Conclusions AVC-101 continues to be safe and tolerable. Repeated dosing of TM in consolidation cycles resulted in robust re-expansion of UniCAR-T with deeper remissions of extended durability. The switchable mechanism provides proven rapid reversal of safety events, enabling higher dose levels.

DIFFERENTIATED HYPEROSMOLARY THERAPY IN CEREBRAL EDEMA IN PATIENTS WITH CRANIOCEREBRAL INJURY

to study the pathophysiological aspects of cerebral edema and compare the effectiveness of using 15% mannitol solution and hypertonic 3.5%, 7%, 10% sodium chloride solution in the complex treatment of patients with head injury. Material and methods:90 patients from 18 years old to 68 years old with various traumatic brain injuries and inhibition of consciousness level from 4 to 13 points on the Glasgow coma scale were examined. Results:infusion of mannitol at the indicated dosage reduced ICP after 30 minutes by 42, 3%, and after 120 minutes it remained below the initial data by 23.9%. Infusion of a 3.5% NaCl solution already by the 30th minute led to a decrease of ICP by 48.6%, and by the end of 120 minutes the ICP remained below the initial data by 35.9%. Infusion of a 7% NaCl solution already by the 30th minute led to a decrease in ICP by 55.4%, and by the end of 120 minutes the ICP remained below the initial data by 39.9%. Infusion of a 10% NaCl solution already by the 30th minute led to a decrease in ICP by 58.4%, and by the end of 120 minutes the ICP remained below the initial data by 45.9%. Conclusions:the decrease in ICP within 30 and 120 minutes after the introduction of hyperosmolar solutions is more pronounced with iv administration of 3.5%, 7%, 10% NaCl solution relative to 15% Mannitol in calculated dosages, which should be borne in mind in patients with concomitant cardiac and renal pathology.

A Minimal PBPK Model for Plasma and Cerebrospinal Fluid Pharmacokinetics of Trastuzumab after Intracerebroventricular Administration in Patients with HER2-Positive Brain Metastatic Localizations.

Dosing regimens of trastuzumab administered by intracerebroventricular (icv) route to patients with HER2-positive brain localizations remain empirical. The objectives of this study were to describe pharmacokinetics (PK) of trastuzumab in human plasma and cerebrospinal fluid (CSF) after simultaneous icv and intravenous (iv) administration using a minimal physiologically-based pharmacokinetic model (mPBPK) and to perform simulations of alternative dosing regimens to achieve therapeutic concentrations in CSF. Plasma and CSF PK data were collected in two patients with HER2-positive brain localizations. A mPBPK model for mAbs consisting of four compartments (tight and leaky tissues, plasma and lymph) was enriched by an additional compartment for ventricular CSF. The comparison between observed and model-predicted concentrations was evaluated using prediction error (PE). The developed mPBPK model described plasma and CSF trastuzumab concentrations reasonably well with mean PE for plasma and CSF data of 41.8% [interquartile range, IQR = -9.48; 40.6] and 18.3% [-36.7; 60.6], respectively, for patient 1 and 11.4% [-10.8; 28.7] and 22.5% [-27.7; 77.9], respectively, for patient 2. Trastuzumab showed fast clearance from CSF to plasma with Cmin,ssof 0.56 and 0.85mg/L for 100 and 150mg q1wk, respectively. Repeated dosing of 100 and 150mg q3day resulted in Cmin,ssof 10.3 and 15.4mg/L, respectively. Trastuzumab CSF target concentrations are achieved rapidly and maintained above 60mg/L from 7days after a continuous perfusion at 1.0mg/h. Continuous icv infusion of trastuzumab at 1.0mg/h could be an alternative dosing regimen to rapidly achieve intraventricular CSF therapeutic concentrations.